Pteridine dione monocarboxylate transporter inhibitors

ABSTRACT

The invention provides compounds effective as inhibitors of monocarboxylate transporters such as MCT1 and MCT4, which can be used for treatment of medical conditions wherein treatment of the condition with a compound having an inhibitor effect on MCT1, MCT4, or both is medically indicated. Compounds of the invention can have antitumor, antidiabetes, anti-inflammatory, or immunosuppressive pharmacological effects, and can be effective for treatment of cancer and of type II diabetes.

CROSS-REFERENCE TO RELATED APPLICATION

This application claims the priority of U.S. Provisional ApplicationSer. No. 62/106,472, filed Jan. 22, 2015, the disclosure of which isincorporated herein by reference in its entirety.

STATEMENT OF GOVERNMENT SUPPORT

This invention was made with government support under RO1 CA154739awarded by the National Institutes of Health. The government has certainrights in the invention.

BACKGROUND

In the 1920s the German biochemist Otto Warburg described metabolicdifferences between cancerous and normal cells, where he noted thattumor cells rely upon a high rate of aerobic glycolysis rather thanoxidative phosphorylation to produce energy for maintenance of cellularfunctions.^(1,2) Indeed, cancer cells have up to a 60-fold enhanced rateof glycolysis relative to normal cells, even with sufficient oxygen.¹This dependence upon glycolysis, and its consequences, is termed “theWarburg effect”.²

Malignant cells are highly anabolic and require very high levelsnutrients, ATP and building blocks to synthesize components needed fortheir growth and survival. Use of the glycolytic pathway provides ATPbut also drives production of lactate, which is produced from pyruvateat the end of the glycolytic pathway. Massive lactate production by thetumor cell requires an efficient means for its consumption orelimination, to prevent intracellular acidification of the cancer cell.

Two mechanisms for handling excess lactate have been described. First,in some rare tumor types lactate is converted to pyruvate for entry intothe TCA cycle. More commonly, however, lactate homeostasis is maintainedvia a family of twelve-membrane pass cell surface proteins known as themonocarboxylate transporters (MCTs; also known as the SLC16a transporterfamily). Fourteen MCTs are known, but only MCT1, MCT2, MCT3 and MCT4transport small monocarboxylates such as lactate, pyruvate and ketonebodies (acetoacetate and β-hydroxybutyrate) across plasma membranes in aproton-linked exchange.³ Expression analyses have established that mostaggressive tumor types express markedly elevated levels of MCT1, MCT4 orboth.⁴ The chaperone protein CD147, which contains immunoglobulin-likedomains, is required for MCT1 and MCT4 cell surface expression and isco-localized with the transporters. MCT1, MCT4 and CD147 are now highpriority targets for cancer therapeutics.⁴

The expression of MCT1 and MCT4 is regulated by two major oncogenictranscription factors, MYC and hypoxia inducible factor-1a (HIF-1α),respectively,^(4,5) that direct marked increases in the production ofkey proteins that support aerobic glycolysis, including amino acidtransporters and enzymes involved in the catabolism of glutamine andglucose.⁶ Malignancies having MYC involvement and hypoxic tumors aregenerally resistant to current frontline therapies, with high rates oftreatment failure, relapse and high patient mortality.^(7,8)Importantly, inhibition of MCT1 or MCT4 can kill tumor cells ex vivo andprovoke tumor regression in vivo,^(4,9) and their potency is augmentedby agents such as metformin that force a glycolytic phenotype upon thecancer cell.⁴

Many weak MCT inhibitors (i.e., those effective at high micromolarlevels) have been described, includingα-cyano-4-hydroxycinnamate^(10,11) stilbene disulfonates,¹² phloretin¹³and related flavonoids.¹⁴ Coumarin-derived covalent MCT inhibitors havealso recently been disclosed,^(15,16) as have pteridinones.¹⁷

The most advanced MCT1 inhibitors are related pyrrolopyrimidine diones,pyrrolopyridazinones, and thienopyrimidine diones,^(18,23) including acompound that has advanced into clinical trials for treating some humanmalignancies.^(24,25) These compounds, and to our knowledge all MCT1inhibitors yet described, are dual MCT1/MCT2 inhibitors. MCT2 has veryhigh sequence homology with MCT1, yet it likely has a lesser role thanMCT1 and MCT4 for monocarboxylate transport in human cancers based uponexpression studies. However, MCT2 inhibition may play a role inpotential off-target effects of current agents that could arise fromblocking lactate transport in normal cells.

The first highly potent MCT inhibitor was initially identified via acell-based assay seeking immunosuppressive agents that inhibitNFAT1-directed IL-2 transcription.²⁶ MCT1 inhibition as its mechanism ofaction was described a full decade later.¹⁸ Several subsequentlypublished analogs are also potent MCT1 inhibitors, with low nanomolar Kivalues for MCT1 inhibition and low nanomolar EC₅₀ values inn MTT assaysfor growth of MCT1-expressing tumors.

In many human tumors MCT1 and MCT4 are inversely expressed. Smallmolecule MCT1 inhibitors are now known to disable tumor cell metabolism,proliferation and survival, and impair tumorigenic potential in vivo intumors expressing high levels of MCT1.⁴ MCT4 inhibitors are likely to besimilarly effective for tumors expressing elevated levels of MCT4.Antitumor effects of MCT1 inhibitors are augmented by co-administrationof the biguanide metformin, which is thought to further augment relianceby tumor cells upon aerobic glycolysis and thus increase the demand toMCT1-mediated efflux of lactate.⁴

In addition to antitumor effects, inhibitors of MCT1 and/or MCT4 mayhave other important biological effects, such as immune suppression,¹⁸anti-inflammatory,²⁶ and anti-diabetic effects.²⁷⁻³² MCT1 is normallyexpressed at very low levels in pancreatic islets and in beta-cells inparticular.²⁷⁻²⁸ This scenario explains the very slow uptake of lactatein these cells.²⁹ A hallmark of exercise-induced hyperinsulinism (EIHI)is inappropriate insulin secretion following vigorous physical activity,which leads to hypoglycemia.³⁰ In a 2012 study, Rutter and co-workersestablished that EIHI is associated with elevated expression of MCT1 inbeta-cells and that transgenic mice engineered to overexpress MCT1 inpart displayed many of the hallmarks of EIH16.³¹ While the link betweenlactate and insulin secretion has been suggested since the late 1980s³²these more recent studies clarify the central role of MCT1 (and perhapsof the related lactate transporters MCT2 and MCT4).

SUMMARY

The invention provides, in various embodiments, a MCT-inhibitorycompound of formula A or of formula B

wherein

R¹ and R² are each independently selected from the group consisting ofhydrogen, (C₁-C₆)alkyl, (C₃-C₆)branched alkyl, (C₃-C₇)cycloalkyl,(C₁-C₆)fluoroalkyl, a (C₆-C₁₀)aryl ring system, a 5- to 9-memberedheteroaryl ring system, a (C₁-C₆)alkyl-(C₆-C₁₀)aryl ring system, and a(C₁-C₆)alkyl-(5- to 9-membered)heteroaryl ring system;

provided that when R² comprises an aryl or heteroaryl ring system, thering system bears 0-2 independently selected substituents from the groupconsisting of fluoro, chloro, trifluoromethyl, (C₁-C₆)alkoxy, and(C₁-C₆)fluoroalkoxy;

E is CH₂, CH(C₁-C₆)alkyl, or CH(C₃-C₇)cycloalkyl;

J is O, S, S(O), S(O)₂, NH, N(C₁-C₆)alkyl, or NC(═O)(C₁-C₆)alkyl;

R³ is a monocyclic or bicyclic (C₆-C₁₀)aryl or a monocyclic or bicyclic(5- to 10-membered) heteroaryl group wherein the aryl or heteroaryl canbe substituted or unsubstituted;

R⁴ is hydrogen, (C₁-C₆)alkyl, (C₃-C₆)branched alkyl, (C₁-C₆)fluoroalkyl,(C₃-C₇)cycloalkyl, a (4- to 7-membered)heteroaryl, or a monocyclic orbicyclic (C₆-C₁₀)aryl or a monocyclic or bicyclic (5- to 10-membered)heteroaryl group wherein the aryl or heteroaryl can be substituted orunsubstituted;

Z is a bond, or is —O—, —CH₂—, —CH(Me)-, —S—, —NH—, or —N(C1-C6)alkyl;

n=1, 2, 3, or 4;

the cyclic group indicated as “ring” is an aryl or heteroaryl group ofany one of the following formulas:

wherein wavy lines indicate points of bonding, and wherein each M is anindependently selected CH or N, provided that M group is a nitrogen atomin one or two instances;

G is S, O, NH, NMe, or NCF₃;

T is independently at each occurrence CH or N;

wherein R⁵ is optionally present, R⁵ being one to four instances ofindependently selected F, Cl, Br, CF₃, (C₁-C₆)alkyl, OCF₃,O(C₁-C₆)alkyl, or CO—(C₁-C₆)alkyl;

or,

the cyclic group indicated as “ring” is a (C₃-C₇)cycloalkyl or asaturated (3- to 7-membered)heterocyclyl comprising 1-2 heteroatomsselected from the group consisting of 0, NH, N(C1-C6)alkyl, andN(C1-C6)fluoroalkyl; wherein the points of bonding may be cis or trans;

or a pharmaceutically acceptable salt thereof.

The invention further provides a pharmaceutical composition comprising acompound of the invention and a pharmaceutically acceptable excipient.

In various embodiments, the invention provides a method of inhibitingmonocarboxylate transporter MCT1, monocarboxylate transporter MCT4, orboth, comprising contacting the monocarboxylate transporter with aneffective amount or concentration of a compound of the invention.

The invention further provides a method of treatment of a condition in amammal wherein treatment of the condition with a compound having aninhibitor effect on MCT1, MCT4, or both is medically indicated,comprising administering an effective amount of a compound of theinvention. For example, the compound can show an antitumor,antidiabetes, anti-inflammatory, or immunosuppressive pharmacologicaleffect.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows pteridine dione inhibitors of MCT of structures A and B.

FIG. 2 shows the general scaffold type, termed a “pteridine dione”, withthe numbering conventions for this ring system and a naming example toillustrate the numbering conventions.

FIG. 3 shows tumor volume results from a mouse tumor xenograft study

FIG. 4 shows final tumor weight results from a mouse tumor xenograftstudy.

FIG. 5 shows the structure of SR-11431, the product of Example 3, usedin the mouse tumor xenograft study referred to in FIGS. 3 and 4.

FIG. 6 shows a graph of a time course study of tumor volume for mice towhom was administered SR-11431 and SR-11431 plus Metformin, versusvehicle.

FIG. 7 shows a comparison of test animal body weights from the study ofFIG. 6 at day 29.

FIG. 8 shows a comparison of tumor weight from the study of FIG. 6 atday 32.

DETAILED DESCRIPTION Definitions

The terms MCT1 and MCT4 refer to monocarboxylate transporter isoform 1and monocarboxylate transporter isoform 4, respectively.

The term “inhibitor” as used herein refers to a compound that binds to atarget and renders it biologically inactive or less active.

The term “heteroatom” as used herein refers to an atom of any elementother than carbon or hydrogen. Common heteroatoms include nitrogen,oxygen, phosphorus, sulfur and selenium.

The abbreviation “CNS” as used herein refers to the central nervoussystem of an organism.

The term “EC₅₀” as used herein refers to the dose of a test compoundwhich produces 50% of its maximum response or effect in an assay.

The term “IC₅₀” as used herein refers to the dose of a test compoundwhich produces 50% inhibition in a biochemical assay.

The term “alkyl” as used herein throughout the specification, examples,and claims refers to a hydrocarbon group, and includes branched chainvariations, or “branched alkyl” groups.

The term “fluoroalkyl” refers to an alkyl group having any chemicallypossible number of fluorine atoms bonded thereto; thus, the termencompasses mono-, di-, and trifluoromethyl, perfluoroalkyl groups, andthe like.

The term “fluoroalkoxy” refers to an alkoxy group having any chemicallypossible number of fluorine atoms bonded thereto; thus, the termencompasses mono-, di-, and trifluoromethoxy, perfluoroalkoxy groups,and the like.

The term “cycloalkyl” as used herein throughout the specification,examples, and claims refers to a cyclic hydrocarbon group, and mayinclude alkyl substituents on the cyclic hydrocarbon group.

The term “substituted alkyl” as used herein refers to alkyl moietieshaving substituents replacing a hydrogen atom on one or more carbonatoms of the hydrocarbon backbone. Such substituents can include, forexample, a halogen, a halogenated alkyl (e.g., CF₃), a hydroxyl, acarbonyl, an amino, an amido, an amidine, an imine, an alkoxy, ahalogenated alkoxy (e.g., OCF₃, OCHF₂, etc.) a cyano, a nitro, an azido,a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, asulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic orheteroaromatic group. It will be understood by those skilled in the artthat the moieties substituted on the hydrocarbon chain can themselves besubstituted, if appropriate.

The term “aryl” and “heteroaryl” as used herein includes 5-, 6- and7-membered single-ring aromatic groups that may include from zero tofour heteroatoms, for example, benzene, pyrrole, furan, thiophene,imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine,pyridazine, pyrimidine, and the like. Those aryl groups havingheteroatoms in the ring structure may also be referred to as “arylheterocycles” or “heteroaromatics.” The aromatic ring can be substitutedat one or more ring positions with such substituents as described above,for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl,hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate,phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl,sulfonamido, ketone, aldehyde, ester, heterocyclyl, aromatic orheteroaromatic moieties, —CF₃, —CN, or the like. The term “aryl” alsoincludes polycyclic ring systems having two or more cyclic rings inwhich two or more carbons are common to two adjoining rings (the ringsare “fused rings”) wherein at least one of the rings is aromatic, e.g.,the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls,aryls and/or heterocyclyls. The terms ortho, meta and para apply to1,2-, 1,3- and 1,4-disubstituted benzenes, respectively. For example,the names “1,2-dimethylbenzene” and “ortho, meta-dimethylbenzene” aresynonymous.

The term “aralkyl” as used herein refers to an alkyl group substitutedwith an aryl group (e.g., an aromatic or heteroaromatic group). Examplesinclude CH₂Ph, CH₂CH₂Ph, CH₂CH₂-indole, and the like. The aromatic ringcan be substituted at one or more ring positions with such substituents,as described above.

Unless the number of carbons is otherwise specified, “lower alkyl” asused herein means an alkyl group, as defined above, but having from oneto ten carbons, more preferably from one to six carbon atoms in itsbackbone structure. Likewise, “lower alkenyl” and “lower alkynyl” havesimilar chain lengths.

The terms “heterocyclyl” or “heterocyclic group” as used herein refer to3- to 10-membered ring structures, more preferably 3- to 7-memberedrings that include one to four heteroatoms. Heterocycles can also bepolycycles. Heterocyclyl groups include, for example, azetidine,azepine, thiophene, furan, pyran, isobenzofuran, chromene, xanthene,phenoxathiin, pyrrole, imidazole, pyrazole, isothiazole, isoxazole,pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole,indole, indazole, purine, quinolizine, isoquinoline, quinoline,phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline,pteridine, carbazole, carboline, phenanthridine, acridine, pyrimidine,phenanthroline, phenazine, phenarsazine, phenothiazine, furazan,phenoxazine, pyrrolidine, oxolane, thiolane, oxazole, piperidine,piperazine, morpholine, lactones, lactams such as azetidinones andpyrrolidinones, sultams, sultones, and the like. The heterocyclic ringcan be substituted at one or more positions with such substituents asdescribed above, as for example, halogen, alkyl, aralkyl, alkenyl,alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido,phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio,sulfonyl, ketone, aldehyde, ester, a heterocyclyl, an aromatic orheteroaromatic moiety, —CF₃, —CN, or the like.

The terms “polycyclyl” or “polycyclic group” refer to two or more rings(e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/orheterocyclyls) in which two or more carbons are common to two adjoiningrings, e.g., the rings are “fused rings”. Rings that are joined throughnon-adjacent atoms are termed “bridged” rings. Each of the rings of thepolycycle can be substituted with such substituents as described above,as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl,hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate,phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl,ketone, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromaticmoiety, —CF₃, —CN, or the like.

The term “carbocycle”, as used herein, refers to an aromatic ornon-aromatic ring in which each atom of the ring is carbon.

As used herein, the term “halogen” designates —F, —Cl, —Br or —I.

As used herein, the term “hydroxyl” means —OH.

As used herein, the term “sulfonyl” means —SO₂—.

The terms “amine” and “amino” as used herein are recognized in the artand refer to both unsubstituted and substituted amines, e.g., a moietythat can be represented by the general formulas —NH₂, —NHR, —NRR″, whereR and R′ are alkyl, cycloalkyl, aryl, or heterocyclyl groups, asexample.

The terms “alkoxyl” or “alkoxy” as used herein refers to an alkyl group,as defined above, having an oxygen radical attached thereto.Representative alkoxyl groups include methoxy, ethoxy, propyloxy,tert-butoxy and the like.

The term “ether” as used herein refers to two hydrocarbons groupscovalently linked by an oxygen atom.

The term “sulfonamido” is art recognized and includes a moiety that canbe represented by the general formula —SO₂—N(R)(R′) wherein where R, andR′ are alkyl, cycloalkyl, aryl, or heterocyclyl groups, as examples.

As used herein, the definition of each expression, e.g., alkyl, m, n,etc., when it occurs more than once in any structure, is intended to beindependent of its definition elsewhere in the same structure.

It will be understood that “substitution” or “substituted with” includesthe implicit proviso that such substitution is in accordance withpermitted valence of the substituted atom and the substituent, and thatthe substitution results in a stable compound, e.g., which does notspontaneously undergo transformation such as by rearrangement,cyclization, elimination, etc.

The phrase “protecting group” as used herein means temporarysubstituents which protect a potentially reactive functional group fromundesired chemical transformations. Examples of such protecting groupsinclude carbamates of amines, esters of carboxylic acids, silyl ethersof alcohols, and acetals and ketals of aldehydes and ketones,respectively. The field of protecting group chemistry has been reviewed(Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis,2nd ed.; Wiley: New York, 1991).

The term “Example” as used herein indicates the procedures followed forthe preparation of a claimed compound, In general, the compounds of thepresent invention may be prepared by the methods illustrated in thegeneral reaction schemes as, for example, described in the examples, orby modifications thereof, using readily available starting materials,reagents and conventional synthesis procedures not mentioned here.

It is understood that certain claimed molecules may stably exist in withisotopic variants among specific substituents, such as deuterium ortritium in the place of hydrogen. Such isotopic variants also fallwithin the scope of the invention.

Certain compounds of the present invention may exist in particulargeometric or stereoisomeric forms. The present invention contemplatesall such compounds, including cis- and trans-isomers, R- andS-enantiomers, diastereomers, (D)-isomers, (L)-isomers, the racemicmixtures thereof, and other mixtures thereof, as falling within thescope of the invention. Additional asymmetric carbon atoms may bepresent in a substituent such as an alkyl group. All such isomers, aswell as mixtures thereof, are intended to be included in this invention.

It is understood that certain groups such as amines bear a net charge.When such a group or groups are present in a “claimed compound”,pharmaceutically acceptable salt forms of the structure are implicitlyencompassed in the claims as well. For example, a claim for a compoundwith one or more amino groups present in the structure also implicitlyclaims all pharmaceutically acceptable salt forms, such ashydrochloride, methanesulfonyl, formate, oxalate, tartrate salts, andthe like.

It is understood that certain “claimed compounds” may stably exist ashydrates or solvates. Such differing forms are also implicitlyencompassed in the claims. Hydrates refer to molecules of water presentin the crystal lattice. Solvates refer to molecules of a relativelybenign solvent, such as ethanol, present in the crystal lattice.

It is understood that certain “claimed compounds” in any form, includingas a salt, hydrate, or solvate, may stably exist in multiple solidcrystalline and/or amorphous forms. Such forms may confer differentphysical properties (e.g., rate of dissolution, stability,hydroscopicity). Such differing solid forms are also implicitlyencompassed in the claims.

The invention provides, in various embodiments, a MCT-inhibitorycompound of formula A or of formula R

wherein

R¹ and R² are each independently selected from the group consisting ofhydrogen, (C₁-C₆)alkyl, (C₃-C₆)branched alkyl, (C₃-C₇)cycloalkyl,(C₁-C₆)fluoroalkyl, a (C₆-C₁₀)aryl ring system, a 5- to 9-memberedheteroaryl ring system, a (C₁-C₆)alkyl-(C₆-C₁₀)aryl ring system, and a(C₁-C₆)alkyl-(5- to 9-membered)heteroaryl ring system;

provided that when R² comprises an aryl or heteroaryl ring system, thering system bears 0-2 independently selected substituents from the groupconsisting of fluoro, chloro, trifluoromethyl, (C₁-C₆)alkoxy, and(C₁-C₆)fluoroalkoxy;

E is CH₂, CH(C₁-C₆)alkyl, or CH(C₃-C₇)cycloalkyl;

J is Q, S, S(O), S(O)₂, NH, N(C₁-C₆)alkyl, or NC(═O)(C₁-C₆)alkyl;

R³ is a monocyclic or bicyclic (C₆-C₁₀)aryl or a monocyclic or bicyclic(5- to 10-membered) heteroaryl group wherein the aryl or heteroaryl canbe substituted or unsubstituted;

R⁴ is hydrogen, (C₁-C₆)alkyl, (C₃-C₆)branched alkyl, (C₁-C₆)fluoroalkyl,(C₃-C₇)cycloalkyl, a (4- to 7-membered)heteroaryl, or a monocyclic orbicyclic (C₆-C₁₀)aryl or a monocyclic or bicyclic (5- to 10-membered)heteroaryl group wherein the aryl or heteroaryl can be substituted orunsubstituted;

Z is a bond, or is —O—, —CH₂—, —CH(Me)-, —S—, —NH—, or —N(C1-C6)alkyl;

n=1, 2, 3, or 4;

the cyclic group indicated as “ring” is an aryl or heteroaryl group ofany one of the following formulas:

wherein wavy lines indicate points of bonding, and wherein each M is anindependently selected CH or N, provided that M group is a nitrogen atomin one or two instances;

G is S, O, NH, N(C₁-C₆)alkyl, or NCF₃.

T is independently at each occurrence CH or N;

wherein R⁵ is optionally present, R⁵ being one to four instances ofindependently selected F, Cl, Br, CF₃, (C₁-C₆)alkyl, OCF₃,O(C₁-C₆)alkyl, or CO—(C₁-C₆)alkyl;

or,

the cyclic group indicated as “ring” is a (C₃-C₇)cycloalkyl or asaturated (3- to 7-membered)heterocyclyl comprising 1-2 heteroatomsselected from the group consisting of O, NH, N(C1-C6)alkyl, andN(C1-C6)fluoroalkyl; wherein the points of bonding may be cis or trans;

or a pharmaceutically acceptable salt thereof.

In various embodiments, R³ is monocyclic, and the core ring system canconsist of 5 or 6 atoms in total, with 1-6 carbon atoms, 0-4 nitrogenatoms, 0-2 oxygen atoms, and 0-1 sulfur atoms. Representative examplesof a monocyclic R³ group include:

wherein X is H, (C₁-C₆)alkyl, or CF₃;

wherein Y is optionally present and, when present, Y is 1-3 instances ofa substituent selected from the group consisting of H, F, Cl, Br, CF₃,(C1-C6)alkyl, NH₂, NHMe, NMe₂, NH(C₁-C₆)alkyl, N((C₁-C₆)alkyl)₂,O(C₁-C₆)alkyl; NH—(CH₂)_(j)—CH₂-Q, and

wherein j=2-6, and Q is one of the following:

wherein a wavy line indicates a point of bonding.

In various embodiments, R³ is a bicyclic group, wherein the core ringsystem can consist of 9 or 10 atoms in total, with 4-10 carbon atoms,0-6 nitrogen atoms, 0-2 oxygen atoms, and 0-2 sulfur atoms.

Examples of 9-atom ring systems include the following:

wherein X is H, (C₁-C₆)alkyl, or CF₃;

wherein Y is optionally present and, when present, Y is 1-3 instances ofa substituent selected from the group consisting of H, F, Cl, Br, CF₃,(C1-C6)alkyl, NH₂, NHMe, NMe₂, NH(C₁-C₆)alkyl, N((C₁-C₆)alkyl)₂,O(C₁-C₆)alkyl; NH—(CH₂)_(j)—CH₂-Q, and

wherein j=2-6, and Q is one of the following:

wherein a wavy line indicates a point of bonding, and wherein the groupor groups Y, when indicated on a bicyclic ring system above, can bepresent on either ring, or in both rings.

Examples of 10-atom ring systems include the following:

wherein X is H, (C₁-C₆)alkyl, or CF₃;

wherein Y is optionally present and, when present, Y is 1-3 instances ofa substituent selected from the group consisting of H, F, Cl, Br, CF₃,(C1-C6)alkyl, NH₂, NHMe, NMe₂, NH(C₁-C₆)alkyl, N((C₁-C₆)alkyl)₂,O(C₁-C₆)alkyl; NH—(CH₂)_(j)—CH₂-Q, and

wherein j=2-6, and Q is one of the following:

wherein a wavy line indicates a point of bonding, and wherein the groupor groups Y, when indicated on a bicyclic ring system above, can bepresent on either ring, or in both rings.

Examples Chemistry Methods

All reactions were performed in flame-dried glassware fitted with rubbersepta under positive pressure of nitrogen or argon, unless otherwisenoted. Tetrahydrofuran, DMF, acetonitrile, and methylene chloride werepurchased from Aldrich and used as received. Commercially availablereagents were used without further purification. Thin layerchromatography (TLC) analyses were performed on pre-coated 250 μM silica60 F254 glass-backed plates. Flash chromatography was performed onpre-packed columns of silica gel (230-400 mesh, 40-63 μm) by CombiFlashwith EA/hexane or MeOH/DCM as eluents. Preparative HPLC was performed ona Shimadzu LC-8A preparative HPLC instrument on SunFire C₁₈ OBD 10 μm(30×250 mm) with CH₃CN+50% MeOH/H₂O+0.1% TFA as eluents to purify thetargeted compounds. LC-MS was performed on Agilent Technologies 1200series analytical HPLC instrument paired with a 6140 quadrupole massspectrometer or with a Thermo Scientific UltiMate 3000 massspectrometer. Analytical HPLC was performed on Agilent technologies 1200series with CH₃CN (Solvent B)/H₂O+0.9% CH₃CN+0.1% TFA (solvent A) aseluents, and the targeted products were detected by UV in the detectionrange of 215-310 nm. ¹H and ¹³C NMR spectra were recorded on a BrukerNMR spectrometer at 400 MHz (H) or 100 MHz (¹³C). Unless otherwisespecified, CDCl₃ was used as the NMR solvent. Resonances were reportedin parts per million downfield from TMS standard, and were referenced toeither the residual solvent peak (typically ¹H: CHCl₃ δ 7.27; ¹³C: CDCl₃δ 77.23).

Certain abbreviations for common chemicals used in the Examples aredefined as follows:

EA=ethyl acetateESI=Electrospray ionization mass spectroscopyNMR=nuclear magnetic resonance spectroscopyDMSO=dimethyl sulfoxide

DMF=N,N-dimethylformamide

Hex=hexanesLC-MS=liquid chromatography-mass spectroscopyHPLC=high performance liquid chromatography

NMO=N-methylmorpholine N-oxide

NMP=N-methyl pyrrolidinoneTEA=triethylamineDIAD=diisopropyl azodicarboxylateTf=trifluoromethansulfonylTFA=trifluoroacetic acid

Certain compounds of the invention can be made from the syntheticintermediate7-(((tert-butyldimethylsilyl)oxy)methyl)-1-isobutyl-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropteridin-6-yltrifluoromethanesulfonate (compound 6), prepared as described in Scheme1 and Example 1. In this case R¹ of structures A and B is equal to Me,R² is equal to i-butyl, E is equal to CH₂, and J=O.

Example 1.7-(((tert-butyldimethylsilyl)oxy)methyl)-1-isobutyl-3-methyl-2,4-dioxo-1,2,3,4-tetrahydro-pteridin-6-yltrifluoromethanesulfonate Step 1

6-Chloro-1-isobutyl-3-methylpyrimidine-2,4(1H,3H)-dione: K₂CO₃ (62.19 g,450.0 mmol) was added to the suspension of6-chloro-3-methylpyrimidine-2,4(1H,3H)-dione (40.14 g, 250.0 mmol) inDMSO (300 mL). The mixture was stirred at room temperature for 5 min,then 1-iodo-2-methylpropane (46.03 g, 250.0 mmol) was added and theresultant mixture was heated to 60° C. for 24 h. More1-iodo-2-methylpropane (4.60 g, 25.0 mmol) was added and stirred for anadditional 24 h. Water was added to quench the reaction, extracted withEA. The combined organic extracts were washed with H₂O and brine, driedover Na₂SO₄. The solvent was removed and the residue was purified byflash column (Hex:EA=4:1 to 3:2) to afford 46.89 g (87%) of6-Chloro-1-isobutyl-3-methylpyrimidine-2,4(1H,3H)-dione as a colorlesssolid. R_(f)=0.25 (hex:EA=4:1); LC-MS (ESI): m/z 217 [M+1]⁺; ¹H NMR (400MHz, CDCl₃) δ (ppm) 0.96 (d, J=6.8 Hz, 6H), 2.16 (sep, J=6.9 Hz, 1H),3.33 (s, 3H), 3.90 (d, J=7.0 Hz, 2H), 5.91 (s, 1H).

Step 2

6-Chloro-1-isobutyl-3-methyl-5-nitropyrimidine-2,4(1H,3H)-dione: H₂SO₄(340 mL) was cooled to 0° C. and added dropwise to6-Chloro-1-isobutyl-3-methylpyrimidine-2,4(1H,3H)-dione (45.40 g, 209.5mmol) at 0° C. Fuming HNO₃ (26.40 g, 419.0 mmol) was added dropwise withvigorous stirring. The resultant mixture was stirred at 0° C. for 1 h,then room temperature for 2 h. Cooled to 0° C. The reaction mixture wasslowly poured into ice, extracted with EA. The combined organic extractswere washed with H₂O, sat′d NaHCO₃, and brine, dried over Na₂SO₄. Thesolvent was removed and the residue was purified by column (hex:EA=6:1)to afford 41.94 g (77%) of6-Chloro-1-isobutyl-3-methyl-5-nitropyrimidine-2,4(1H,3H)-dione as ayellow solid. R_(f)=0.30 (hex:EA=4:1); ¹H NMR (400 MHz, CDCl₃) δ (ppm)1.01 (d, J=6.8 Hz, 6H), 2.19 (sep, J=6.8 Hz, 1H), 3.42 (s, 3H), 4.01 (d,J=7.6 Hz, 2H).

Step 3

MethylO-(tert-butyldimethylsilyl)-N-(3-isobutyl-1-methyl-5-nitro-2,6-dioxo-1,2,3,6-tetrahydro-pyrimidin-4-yl)serinate:A mixture of6-Chloro-1-isobutyl-3-methyl-5-nitropyrimidine-2,4(1H,3H)-dione (18.32g, 70.0 mmol), methyl O-(tert-butyldimethylsilyl)serinate (17.97 g, 77.0mmol), Na₂CO₃ (18.55 g, 175.0 mmol) in DMF (140 mL) was heated to 65° C.for 1 h. The reaction mixture was cooled to room temperature, quenchedwith saturated NH₄Cl, extracted with EA. The combined organic extractswere washed with brine three times and dried over Na₂SO₄. The solventwas removed and the residue was purified by column (hex:EA=3:2 to 1:1)to afford 24.62 g (76%) of methylO-(tert-butyldimethylsilyl)-N-(3-isobutyl-1-methyl-5-nitro-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl)serinateas a yellow solid. R_(f)=0.60 (hex:EA=1:1); LC-MS (ESI): m/z 459 [M+1]⁺;¹H NMR (400 MHz, CDCl₃) δ (ppm) 0.01 (s, 6H), 0.83 (s, 9H), 0.97 (d,J=6.8 Hz, 6H), 2.17 (sep, J=6.8 Hz, 1H), 3.33 (s, 3H), 3.70 (s, 1H),3.77-4.10 (m, 5H).

Step 4

7-(((tert-butyldimethylsilyl)oxy)methyl)-1-isobutyl-3-methyl-1,5,7,8-tetrahydropteridine-2,4,6(3H)-trione:A solution of methylO-(tert-butyldimethylsilyl)-N-(3-isobutyl-1-methyl-5-nitro-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4H)serinate(24.62 g, 53.69 mmol) in AcOH (322 mL) was heated to 80° C. under N₂.Zinc (42.12 g, 644.0 mmol) was added portionwise. The resultant mixturewas stirred at 80° C. for 30 min. The reaction was cooled to roomtemperature and filtered. The filtrate was concentrated. The residue wasdissolved in EA, washed with H₂O, saturated NaHCO₃, and brine, driedover Na₂SO₄. The solvent was removed to afford 23.94 g of7-(((tert-butyldimethylsilyl)oxy)methyl)-1-isobutyl-3-methyl-1,5,7,8-tetrahydropteridine-2,4,6(3H)-trioneas an orange oil, which was used directly for the next step. LC-MS(ESI): m/z 397 [M+1]⁺.

Step 5

7-(((tert-butyldimethylsilyl)oxy)methyl)-1-isobutyl-3-methyl-1,5-dihydropteridine-2,4,6(3H)-trione:A solution of7-(((tert-butyldimethylsilyl)oxy)methyl)-1-isobutyl-3-methyl-1,5,7,8-tetrahydropteridine-2,4,6(3H)-trione(23.94 g) in CH₃CN (430 mL) was treated with DDQ (12.19 g, 53.69 mmol)portionwise. The reaction mixture was stirred at room temperature for anadditional 1 h. The precipitate was collected by filtration to afford16.40 g (77% for 2 steps) of7-(((tert-butyldimethylsilyl)oxy)methyl)-1-isobutyl-3-methyl-1,5-dihydropteridine-2,4,6(3H)-trioneas a yellow solid. LC-MS (ESI): m/z 395 [M+1]⁺; ¹H NMR (400 MHz, CDCl₃)δ (ppm) 0.00 (s, 6H), 0.78 (d, J=6.8 Hz, 6H), 0.83 (s, 9H), 2.13 (sep,J=6.8 Hz, 1H), 3.34 (s, 3H), 4.03 (d, J=7.2 Hz, 2H), 4.90 (s, 2H).

Step 6

The product of Example 1:7-(((tert-butyldimethylsilyl)oxy)methyl)-1-isobutyl-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropteridin-6-yltrifluoromethanesulfonate: A suspension of7-(((tert-butyldimethylsilyl)oxy)methyl)-1-isobutyl-3-methyl-1,5-dihydropteridine-2,4,6(3H)-trione(5.77 g, 14.63 mmol) in CH₂Cl₂ (120 mL) was cooled to 0° C. under N₂.TEA (4.44 g, 43.89 mmol) was added followed by Tf₂O (7.43 g, 26.33mmol). The resultant mixture was stirred at 0° C. for 1 h, diluted withEA, washed with brine, dried over Na₂SO₄. The solvent was removed andthe residue was purified by column (Hex:EA=4:1) to afford 5.07 g (66%)of7-(((tert-butyldimethylsilyl)oxy)methyl)-1-isobutyl-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropteridin-6-yltrifluoromethanesulfonate as a yellow oil. LC-MS (ESI): m/z 527 [M+1]⁺;¹H NMR (400 MHz, CDCl₃) δ (ppm) 0.00 (s, 6H), 0.78-0.81 (m, 15H), 2.10(sep, J=6.8 Hz, 1H), 3.37 (s, 3H), 4.04 (d, J=7.2 Hz, 2H), 4.80 (s, 2H);¹⁹F NMR (400 MHz, CDCl₃) δ (ppm) −71.6.

Certain compounds of the invention were made using the product ofExample 1 as the starting material and following the procedures ofGeneral Scheme 2:

The following compounds were made according to the methods of GeneralScheme 2:

TABLE 1 example chemical structure type groups present 2

A R¹ = Me, R² = i-Bu, R⁴ = H, Z = CH₂, n = 3, E = CH₂, J = O,  

3

A R¹ = Me, R² = i-Bu, R⁴ = H, Z = CH₂, n = 3, E = CH₂, J = O,  

4

A R¹ = Me, R² = i-Bu, R⁴ = H, Z = CH₂, n = 3, E = CH₂, J = O,  

5

A R¹ = Me, R² = i-Bu, R⁴ = H, Z = CH₂, n = 3, E = CH₂, J = O,  

6

A R¹ = Me, R² = i-Bu, R⁴ = H, Z = CH₂, n = 3, E = CH₂, J = O,  

7

A R¹ = Me, R² = i-Bu, R⁴ = H, Z = CH₂, n = 3, E = CH₂, J = O,  

8

A R¹ = Me, R² = i-Bu, R⁴ = H, Z = CH₂, n = 3, E = CH₂, J = O,  

9

A R¹ = Me, R² = i-Bu, R⁴ = H, Z = CH₂, n = 3, E = CH₂, J = O,  

10

A R¹ = Me, R² = i-Bu, R⁴ = H, Z = CH₂, n = 3, E = CH₂, J = O,  

11

A R¹ = Me, R² = i-Bu, R⁴ = H, Z = CH₂, n = 3, E = CH₂, J = O,  

12

A R¹ = Me, R² = i-Bu, R⁴ = H, Z = CH₂, n = 3, E = CH₂, J = O,  

13

A R¹ = Me, R² = i-Bu, R⁴ = H, Z = CH₂, n = 3, E = CH₂, J = O,  

14

A R¹ = Me, R² = i-Bu, R⁴ = H, Z = CH₂, n = 3, E = CH₂, J = O,  

15

A R¹ = Me, R² = i-Bu, R⁴ = H, Z = CH₂, n = 3, E = CH₂, J = O,  

16

A R¹ = Me, R² = i-Bu, R⁴ = H, Z = CH₂, n = 3, E = CH₂, J = O,  

17

A R¹ = Me, R² = i-Bu, R⁴ = H, Z = CH₂, n = 3, E = CH₂, J = O,  

18

A R¹ = Me, R² = i-Bu, R⁴ = H, Z = CH₂, n = 3, E = CH₂, J = O,  

19

A R¹ = Me, R² = i-Bu, R⁴ = H, Z = CH₂, n = 3, E = CH₂, J = O,  

20

A R¹ = Me, R² = i-Bu, R⁴ = H, Z = CH₂, n = 3, E = CH₂, J = O,  

21

A R¹ = Me, R² = i-Bu, R⁴ = H, Z = CH₂, n = 3, E = CH₂, J = O,  

22

A R¹ = Me, R² = i-Bu, R⁴ = H, Z = CH₂, n = 3, E = CH₂, J = O,  

23

A R¹ = Me, R² = i-Bu, R⁴ = H, Z = CH₂, n = 3, E = CH₂, J = O,  

24

A R¹ = Me, R² = i-Bu, R⁴ = H, Z = CH₂, n = 3, E = CH₂, J = O,  

25

A R¹ = Me, R² = i-Bu, R⁴ = H, Z = CH₂, n = 3, E = CH₂, J = O,  

26

A R¹ = Me, R² = i-Bu, R⁴ = H, Z = CH₂, n = 3, E = CH₂, J = O,  

27

A R¹ = Me, R² = i-Bu, R⁴ = H, Z = CH₂, n = 3, E = CH₂, J = O,  

28

A R¹ = Me, R² = i-Bu, R⁴ = H, Z = CH₂, n = 3, E = CH₂, J = O,  

29

A R¹ = Me, R² = i-Bu, R⁴ = H, Z = CH₂, n = 3, E = CH₂, J = O,  

30

A R¹ = Me, R² = i-Bu, R⁴ = H, Z = CH₂, n = 3, E = CH₂, J = O,  

31

A R¹ = Me, R² = i-Bu, R⁴ = H, Z = CH₂, n = 3, E = CH₂, J = O,  

32

A R¹ = Me, R² = i-Bu, R⁴ = H, Z = CH₂, n = 3, E = CH₂, J = O,  

33

A R¹ = Me, R² = i-Bu, R⁴ = H, Z = CH₂, n = 3, E = CH₂, J = O,  

34

A R¹ = Me, R² = i-Bu, R⁴ = H, Z = CH₂, n = 3, E = CH₂, J = O,  

Example 2.6-(5-hydroxypentyl)-1-isobutyl-3-methyl-7-((naphthalen-1-yloxy)methyl)pteridine-2,4(1H,3H)-dione

Step 1

5-7-(((tert-butyldimethylsilyl)oxy)methyl)-1-isobutyl-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropteridin-6-yl)pent-4-yn-1-ylacetate: A mixture of7-(((tert-butyldimethylsilyl)oxy)methyl)-1-isobutyl-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropteridin-6-yltrifluoromethanesulfonate (5.07 g, 9.63 mmol), pent-4-yn-1-yl acetate(2.19 g, 17.33 mmol), and CuI (275 mg, 1.44 mmol) in DMF (144 mL) wasdegassed. Pd(PPh₃)₄ (556 mg, 0.482 mmol) was added followed by TEA (5.85g, 57.78 mmol), and degassed. The reaction was stirred at 100° C. for1.5 hours, then cooled to room temperature. The reaction was quenchedwith saturated NH₄Cl, extracted with EA. The combined organic extractswere washed with brine, dried over Na₂SO₄. The solvent was removed andthe residue was purified by column (Hex:EA=2:1) to afford 2.32 g (48%)of5-7-(((tert-butyldimethylsilyl)oxy)methyl)-1-isobutyl-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropteridin-6-yl)pent-4-yn-1-ylacetateas a yellow oil. R_(f)=0.55 (Hex:EA=1:1); LC-MS (ESI): m/z 503 [M+1]⁺.¹H NMR (400 MHz, CDCl₃) δ (ppm) s (0.00, 6H), 0.79 (d, J=6.8 Hz, 6H),0.81 (s, 9H), 1.81-8.92 (m, 4H), 1.93 (s, 3H), 2.14 (sep, J=6.8 Hz, 1H),2.47 (t, J=7.0 Hz, 2H), 3.39 (s, 3H), 4.07-4.10 (m, 2H), 4.87 (s, 2H).

Step 2

5-7-(hydroxymethyl)-1-isobutyl-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropteridin-6-yl)pent-4-yn-1-ylacetate: A solution of5-7-(((tert-butyldimethylsilyl)oxy)methyl)-1-isobutyl-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropteridin-6-yl)pent-4-yn-1-ylacetate(1.485 g, 2.95 mmol) in THF (100 mL) was treated with a solution of TsOH(0.45 g, 2.36 mmol) in H₂O (20 mL). The reaction was stirred at roomtemperature for 24 hours. The reaction was diluted with EA, washed withbrine, dried over Na₂SO₄. The solvent was removed and the residue waspurified by column (Hex:EA=2:1) to afford 924 mg (81%) of5-7-(hydroxymethyl)-1-isobutyl-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropteridin-6-yl)pent-4-yn-1-ylacetate as a pink solid. R_(f)=0.25 (Hex:EA=1:1); LC-MS (ESI): m/z 389[M+1]⁺. ¹H NMR (400 MHz, CDCl₃) δ (ppm) 0.97 (d, J=6.8 Hz, 6H),1.99-2.03 (m, 2H), 2.10 (s, 3H), 2.27 (sep, J=6.8 Hz, 1H), 2.64 (t,J=7.2 Hz, 2H), 3.56 (s, 3H), 4.21-4.26 (m, 4H), 5.00 (d, J=4.8 Hz, 2H);¹³C NMR (100 MHz, CDCl₃) δ (ppm) 20.2, 21.0, 25.9, 27.5, 28.0, 28.4,29.1, 32.6, 49.5, 61.8, 64.2, 125.4, 145.5, 150.2, 150.6, 156.0, 160.0,171.2.

Step 3 (Version 3A)

5-(1-isobutyl-3-methyl-7-((naphthalen-1-yloxy)methyl)-2,4-dioxo-1,2,3,4-tetrahydropteridin-6-yl)pent-4-yn-1-ylacetate: A mixture of5-7-(hydroxymethyl)-1-isobutyl-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropteridin-6-yl)pent-4-yn-1-ylacetate(165 mg, 0.425 mmol), naphthalen-1-ol (612 mg, 4.25 mmol), and PPh₃ (669mg, 2.55 mmol) in THF (15 mL) was treated with DEAD (555 mg, 40% wtsolution in toluene, 1.28 mmol). The reaction was stirred at roomtemperature for 24 hours. The reaction was diluted with EA, washed withbrine, dried over Na₂SO₄. The solvent was removed and the residue waspurified by column (Hex:EA=3:2) to afford5-(1-isobutyl-3-methyl-7-((naphthalen-1-yloxy)methyl)-2,4-dioxo-1,2,3,4-tetrahydropteridin-6-yl)pent-4-yn-1-ylacetate as a yellow solid. R_(f)=0.40 (Hex:EA=1:1); LC-MS (ESI): m/z 515[M+1]⁺. ¹H NMR (400 MHz, CDCl₃) δ (ppm) 0.64 (d, J=6.4 Hz, 6H),1.85-1.97 (m, 3H), 2.06 (s, 3H), 2.55 (t, J=7.0 Hz, 2H), 3.52 (s, 3H),3.94 (d, J=7.6 Hz, 2H), 4.15 (t, J=6.2 Hz, 2H), 5.64 (s, 2H), 6.80 (d,J=7.6 Hz, 1H), 7.31-7.54 (m, 4H), 7.81 (d, J=7.2 Hz, 1H), 8.35 (d, J=7.2Hz, 1H).

Step 4 (Version 4A)

5-(1-isobutyl-3-methyl-7-((naphthalen-1-yloxy)methyl)-2,4-dioxo-1,2,3,4-tetrahydropteridin-6-yl)pentylacetate: A mixture of5-(1-isobutyl-3-methyl-7-((naphthalen-1-yloxy)methyl)-2,4-dioxo-1,2,3,4-tetrahydropteridin-6-yl)pent-4-yn-1-ylacetate(50 mg, 0.097 mmol) and Pd/C (30 mg, 10% on charcoal) in MeOH (10 mL)was stirred under H₂ (Parr hydrogenator, 50 psi) for 1 hour. Thereaction was filtered. The filtrate was concentrated and purified bycolumn (Hex:EA=3:2) to afford 44 mg (87%) of5-(1-isobutyl-3-methyl-7-((naphthalen-1-yloxy)methyl)-2,4-dioxo-1,2,3,4-tetrahydropteridin-6-yl)pentylacetate as a yellow solid. R_(f)=0.40 (Hex:EA=1:1); LC-MS (ESI): m/z 519[M+1]⁺. ¹H NMR (400 MHz, CDCl₃) δ (ppm) 0.84 (d, J=6.4 Hz, 6H),1.46-1.51 (m, 2H), 1.60-1.69 (m, 2H), 1.85-1.91 (m, 2H), 2.03 (s, 3H),2.14 (sep, J=6.8 Hz, 1H), 3.09 (t, J=7.2 Hz, 2H), 3.55 (s, 3H), 4.01 (t,J=6.4 Hz, 2H), 4.09 (d, J=7.6 Hz, 2H), 5.52 (s, 2H), 6.90 (d, J=7.6 Hz,1H), 7.34-7.55 (m, 4H), 7.83 (d, J=7.2 Hz, 1H), 8.25 (d, J=8.0 Hz, 1H).

Step 5

6-(5-hydroxypentyl)-1-isobutyl-3-methyl-7-((naphthalene-1-yloxy)methyl)pteridine-2,4(1H,3H)-dione:A solution of5-(1-isobutyl-3-methyl-7-((naphthalen-1-yloxy)methyl)-2,4-dioxo-1,2,3,4-tetrahydropteridin-6-yl)pentylacetate (8 mg, 0.015 mmol) in THF (3 mL) and MeOH (3 mL) was treatedwith K₂CO₃ (9 mg, 0.060 mmol). The reaction was stirred at roomtemperature for 2 hours. The reaction was diluted with EA, washed withbrine, dried over Na₂SO₄. The filtrate was concentrated and purified bypreparative HPLC to afford 4 mg of6-(5-hydroxypentyl)-1-isobutyl-3-methyl-7-((naphthalene-1-yloxy)methyl)pteridine-2,4(1H,3H)-dioneas a white solid. R_(f)=0.15 (Hex:EA=1:1); Single peak in analyticalHPLC; LC-MS (ESI): m/z 477 [M+1]⁺. ¹H NMR (400 MHz, CDCl₃) δ (ppm) 0.73(d, J=6.4 Hz, 6H), 1.39-1.48 (m, 4H), 1.80-1.91 (m, 2H), 2.04 (sep,J=6.8 Hz, 1H), 3.02 (t, J=7.2 Hz, 2H), 3.45 (s, 3H), 3.54 (t, J=6.4 Hz,2H), 4.00 (d, J=7.2 Hz, 2H), 5.43 (s, 2H), 6.80 (d, J=7.6 Hz, 1H),7.24-7.45 (m, 4H), 7.75 (d, J=7.6 Hz, 1H), 8.16 (d, J=7.6 Hz, 1H).

Example 3.6-(5-hydroxypentyl)-1-isobutyl-7-((isoquinolin-5-yloxy)methyl)-3-methylpteridine-2,4(1H,3H)-dione

Prepared following the methods of Example 2, with the exception of theswitching of steps 3 and 4, with reduction (step 3B) preceding Mitsunobureaction with 5-hydroxyisoquinoline (step 4B), which was followed byacetate removal (step 5) under conditions of KCN/95% ethanol.

Steps 1-2: As in Example 2 Step 3B as in Step 4 of Example 2

5-(7-(hydroxymethyl)-1-isobutyl-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropteridin-6-yl)pentylacetate: A mixture of5-7-(hydroxymethyl)-1-isobutyl-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropteridin-6-yl)pent-4-yn-1-ylacetate(1.218 g, 3.14 mmol) and Pd/C (340 mg, 10% on charcoal) in THF (14 mL)and MeOH (70 mL) was stirred under H₂ (Parr hydrogenator, 50 psi) for 3hours. The reaction was filtered. The filtrate was concentrated andpurified by column (Hex:EA=3:2) to afford 789 mg (64%) of5-(7-(hydroxymethyl)-1-isobutyl-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropteridin-6-yl)pentylacetate as a yellow solid. R_(f)=0.15 (Hex:EA=1:1); LC-MS (ESI): m/z 393[M+1]⁺. ¹H NMR (400 MHz, CDCl₃) δ (ppm) 0.94 (d, J=6.8 Hz, 6H),1.46-1.51 (m, 2H), 1.64-1.72 (m, 2H), 1.76-1.84 (m, 2H), 2.05 (s, 3H),2.25 (sep, J=6.8 Hz, 1H), 2.84 (t, J=8.0 Hz, 2H), 3.54 (s, 3H), 4.06 (t,J=6.6 Hz, 2H), 4.018 (d, J=7.6 Hz, 2H), 4.91 (s, 2H).

Step 4B, as in Step 3 of Example 2, with Slightly Modified MitsunobuConditions

5-(1-isobutyl-7-((isoquinolin-5-yloxy)methyl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropteridin-6-yl)pentylacetate: A mixture of5-(7-(hydroxymethyl)-1-isobutyl-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropteridin-6-yl)pentylacetate (981 mg, 2.50 mmol), 5-hydroxyisoquinoline (435 mg, 3.00 mmol),and PPh₃ (918 mg, 3.50 mmol) in THF (100 mL) was treated with DIAD (708mg, 3.50 mmol). The reaction was stirred at room temperature for 24hours. The reaction was diluted with EA, washed with brine, and driedover Na₂SO₄. The solvent was removed and the residue was purified bycolumn (Hex:EA=2:3) to afford 1.071 g (82%) of5-(1-isobutyl-7-((isoquinolin-5-yloxy)methyl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropteridin-6-yl)pentylacetate as a white solid. R_(f)=0.20 (EA); LC-MS (ESI): m/z 520 [M+1]⁺.

Step 5

6-(5-hydroxypentyl-1-isobutyl-3-methyl-7-((isoquinolin-5-yloxy)methyl)pteridine-2,4-(1H,3H)-dione:A solution of5-(1-isobutyl-3-methyl-2,4-dioxo-7-((isoquinolin-5-yloxy)methyl)-1,2,3,4-tetrahydropteridin-6-yl)pentylacetate (790 mg, 1.52 mmol) in 95% EtOH (100 mL) was treated with KCN(800 mg). The reaction was stirred at room temperature for 40 hours. Thereaction was concentrated and purified by preparative HPLC to afford 326mg (45%) of6-(5-hydroxypentyl-1-isobutyl-3-methyl-7-((isoquinolin-5-yloxy)methyl)pteridine-2,4-(1H,3H)-dioneas white solid (TFA salt). Single peak in analytical HPLC; LC-MS (ESI):m/z 478 [M+1]⁺. ¹H NMR (400 MHz, CDCl₃) δ (ppm) 0.79 (d, J=6.8 Hz, 6H),1.49-1.62 (m, 4H), 1.88-1.93 (m, 2H), 2.08 (sep, J=6.8 Hz, 1H), 3.10 (t,J=7.6 Hz, 2H), 3.54 (s, 3H), 3.66 (t, J=6.2 Hz, 2H), 4.06 (d, J=7.6 Hz,2H), 5.54 (s, 2H), 6.95 (d, J=7.6 Hz, 1H), 7.42-7.45 (m, 1H), 7.60 (t,J=8.2 Hz, 1H), 7.77 (d, J=8.4 Hz, 1H), 8.60 (d, J=8.4 Hz, 1H), 8.95 (s,1H).

Example 4.6-(5-hydroxypentyl)-1-isobutyl-7-((isoquinolin-4-yloxy)methyl)-3-methylpteridine-2,4(1H,3H)-dione

Step 4B Product,5-(1-isobutyl-3-methyl-2,4-dioxo-7-((quinolin-4-yloxy)methyl)-1,2,3,4-tetrahydropteridin-6-yl)pentylacetate

White solid. R_(f)=0.20 (EA); LC-MS (ESI): m/z 520 [M+1]⁺. ¹H NMR (400MHz, CDCl₃) δ (ppm) 0.63 (d, J=6.0 Hz, 6H), 1.40-1.50 (m, 2H), 1.55-1.64(m, 2H), 1.79-1.90 (m, 3H), 1.90 (s, 3H), 2.99 (s, 2H), 3.46 (s, 3H),3.85 (d, J=6.0 Hz, 2H), 3.98 (s, 2H), 5.76 (s, 2H), 7.30 (s, 1H),7.73-7.77 (m, 1H), 7.95-7.98 (m, 1H), 8.31 (d, J=8.0 Hz, 1H), 8.42 (d,J=8.8 Hz, 1H), 9.10 (s, 1H).

Step 5 (final) product,6-(5-hydroxypentyl-1-isobutyl-3-methyl-7-((quinolin-4-yloxy)methyl)pteridine-2,4-(1H,3H)-dione(acetate removal conditions: K₂CO₃, THF, room temperature, 1 h): Whitesolid (TFA salt). Single peak in analytical HPLC; LC-MS (ESI): m/z 478[M+1]+¹H NMR (400 MHz, CDCl₃) δ (ppm) 0.60 (d, J=6.8 Hz, 6H), 1.40-1.60(m, 4H), 1.80-1.89 (m, 2H), 1.92 (sep, J=6.8 Hz, 1H), 2.98 (s, 2H), 3.44(s, 3H), 3.58 (s, 2H), 3.83 (d, J=7.6 Hz, 2H), 5.79 (s, 2H), 7.28 (s,1H), 7.72-7.76 (m, 1H), 7.93-7.97 (m, 1H), 8.31-8.33 (m, 2H) 9.08 (s,1H).

Example 5.6-(5-hydroxypentyl-1-isobutyl-7-((isoquinolin-4-yloxy)methyl)-3-methyl-pteridine-2,4-(1H,3H)-dione

Follows Example 3 using the appropriate heteroaryl alcohol in theMitsunobu step. Step 4B product,5-(1-isobutyl-7-((isoquinolin-4-yloxy)methyl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropteridin-6-yl)pentylacetate:

Yellow solid. R_(f)=0.10 (Hex:EA=1:1); LC-MS (ESI): m/z 520 [M+1]⁺.

Step 5 (final) product6-(5-hydroxypentyl-1-isobutyl-7-((isoquinolin-4-yloxy)methyl)-3-methyl-pteridine-2,4-(1H,3H)-dione:white solid (TFA salt). Single peak in analytical HPLC; LC-MS (ESI): m/z478 [M+1]⁺. ¹H NMR (400 MHz, CD₃OD) δ (ppm) 0.48 (d, J=6.8 Hz, 6H),1.42-1.51 (m, 4H), 1.75-1.88 (m, 3H), 2.97 (t, J=7.8 Hz, 2H), 3.62 (s,3H), 3.45 (t, J=6.4 Hz, 2H), 3.76 (d, J=7.6 Hz, 2H), 5.81 (s, 2H),7.90-7.95 (m, 1H), 8.04-8.08 (m, 1H), 8.21 (s, 1H), 8.32 (d, J=8.4 Hz,1H), 8.43 (d, J=8.4 Hz, 1H), 9.23 (s, 1H).

Example 6.7-(((1H-indol-4-yl)oxy)methyl)-6-(5-hydroxypentyl)-1-isobutyl-3-methylpteridine-2,4(1H,3H)-dione

Follows Example 3 using the appropriate heteroaryl alcohol in theMitsunobu step. Step 4B product,5-(7-(((1H-indol-4-yl)oxy)methyl)-1-isobutyl-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropteridin-6-yl)pentylacetate:

colorless oil. R_(f)=0.30 (Hex:EA=1:1); LC-MS (ESI): m/z 508 [M+1]⁺.

Step 5 (final) product7-(((1H-indol-4-yl)oxy)methyl)-6-(5-hydroxypentyl)-1-isobutyl-3-methylpteridine-2,4-(1H,3H)-dione:brown solid (TFA salt). Single peak in analytical HPLC; LC-MS (ESI): m/z466 [M+1]⁺. ¹H NMR (400 MHz, CD₃OD) δ (ppm) 0.68 (d, J=6.8 Hz, 6H),1.36-1.45 (m, 4H), 1.72-1.77 (m, 2H), 1.96 (sep, J=6.8 Hz, 1H), 2.97 (t,J=8.0 Hz, 2H), 3.36 (s, 3H), 3.41 (t, J=6.4 Hz, 2H), 3.93 (d, J=7.6 Hz,2H), 5.43 (s, 2H), 6.39-6.43 (m, 2H), 6.84-7.03 (m, 3H); ¹³C NMR (100MHz, CDCl₃) δ (ppm) 19.9, 25.4, 27.2, 28.4, 29.0, 32.3, 33.4, 49.3,62.4, 68.8, 99.8, 100.8, 105.3, 118.7, 122.5, 123.1, 125.9, 137.5,145.7, 150.7, 151.6, 152.9, 153.8, 160.4.

Example 7.6-(5-hydroxypentyl)-1-isobutyl-3-methyl-7-((2-(trifluoromethyl)phenoxy)methyl)pteridine-2,4(1H,3H)-dione

Follows Example 3 using the appropriate heteroaryl alcohol in theMitsunobu step. Step 4B product,5-(1-isobutyl-3-methyl-2,4-dioxo-7-((2-trifluoromethyl)phenoxy)methyl)-1,2,3,4-tetrahydropteridin-6-yl)pentylacetate:

Colorless oil. R_(f)=0.40 (Hex:EA=1:1); LC-MS (ESI): m/z 537 [M+1]⁺.

Step 5 (final) product6-(5-hydroxypentyl)-1-isobutyl-3-methyl-7-((2-(trifluoromethyl)phenoxy)methyl)pteridine-2,4-(1H,3H)-dione:white solid. Single peak in analytical HPLC; LC-MS (ESI): m/z 495[M+1]⁺. ¹H NMR (400 MHz, CDCl₃) δ (ppm) 0.84 (d, J=6.8 Hz, 6H),1.50-1.70 (m, 4H), 1.85-1.93 (m, 2H), 2.07 (sep, J=6.8 Hz, 1H), 3.06 (t,J=7.6 Hz, 2H), 3.53 (s, 3H), 3.70 (t, J=5.6 Hz, 2H), 4.08 (d, J=7.6 Hz,2H), 5.43 (s, 2H), 7.03-7.10 (m, 2H), 7.43 (dt, J=1.2, 7.8 Hz, 1H), 7.63(dd, J=1.2, 7.6 Hz, 1H); ¹⁹F NMR (400 MHz, CDCl₃) δ (ppm) −62.1; ¹³C NMR(100 MHz, CDCl₃) δ (ppm) 19.8, 25.4, 27.0, 27.8, 29.0, 32.2, 33.0, 49.2,62.3, 68.6, 112.9, 119.0, 121.0, 122.1, 124.8, 126.1, 127.5, 133.2,145.8, 150.6, 152.2, 155.8, 160.2.

Example 8.6-(5-hydroxypentyl)-1-isobutyl-3-methyl-7-(((4-nitronaphthalen-1-yl)oxy)methyl)pteridine-2,4(1H,3H)-dione

Follows Example 3 using the appropriate heteroaryl alcohol in theMitsunobu step. Step 4B product,5-(1-isobutyl-3-methyl-7-(((4-nitronaphthalen-1-yl)oxy)methyl)-2,4-dioxo-1,2,3,4-tetrahydropteridin-6-yl)pentylacetate:

Yellow solid. R_(f)=0.20 (Hex:EA=1:1); LC-MS (ESI): m/z 564 [M+1]⁺. (400MHz, CDCl₃) δ (ppm) 0.77 (d, J=6.8 Hz, 6H), 1.45-1.54 (m, 2H), 1.60-1.70(m, 2H), 1.83-1.92 (m, 2H), 2.04 (s, 3H), 2.08 (sep, J=6.4 Hz, 1H), 3.08(t, J=8.0 Hz, 2H), 3.54 (s, 3H), 4.02-4.05 (m, 4H), 5.65 (s, 2H), 6.93(d, J=8.4 Hz, 1H), 7.62-7.66 (m, 1H), 7.77-7.81 (m, 1H), 8.34 (d, J=8.8Hz, 1H), 8.40 (d, J=8.0 Hz, 1H), 8.77 (d, J=8.8 Hz, 1H).

Step 5 (final) product6-(5-hydroxypentyl)-1-isobutyl-3-methyl-7-(((4-nitronaphthalen-1-yl)oxy)methylpteridine-2,4-(1H,3H)-dione(acetate removal conditions: K₂CO₃, MeOH, room temperature, 1 h): yellowsolid. >95% purity in analytical HPLC; LC-MS (ESI): m/z 492 [M+1]⁺. ¹HNMR (400 MHz, CDCl₃) δ (ppm) 0.67 (d, J=6.8 Hz, 6H), 1.40-1.54 (m, 4H),1.75-1.86 (m, 2H), 1.97 (sep, J=6.4 Hz, 1H), 3.00 (t, J=7.6 Hz, 2H),3.45 (s, 3H), 3.57 (t, J=6.2 Hz, 2H), 3.93 (d, J=7.2 Hz, 2H), 5.55 (s,2H), 6.82 (d, J=8.8 Hz, 1H), 7.53-7.57 (m, 1H), 7.68-7.72 (m, 1H), 8.26(d, J=8.8 Hz, 1H), 8.32 (d, J=8.4 Hz, 1H), 8.69 (d, J=8.8 Hz, 1H).

Example 9.7-(((4-aminonaphthalen-1-yl)oxy)methyl)-6-(5-hydroxypentyl)-1-isobutyl-3-methylpteridine-2,4(1H,3H)-dione

Prepared from the product of Example 8 by catalytic hydrogenation usingPd/C. Data: light brown solid (TFA salt). Single peak in analyticalHPLC; LC-MS (ESI): m/z 522 [M+1]⁺.¹H NMR (400 MHz, CDCl₃) δ (ppm) 0.60(d, J=6.8 Hz, 6H), 1.36-1.46 (m, 4H), 1.72-1.85 (m, 2H), 1.93 (sep,J=6.4 Hz, 1H), 2.97 (t, J=7.8 Hz, 2H), 3.77 (s, 3H), 3.42 (t, J=6.4 Hz,2H), 3.87 (d, J=7.6 Hz, 2H), 5.56 (s, 2H), 6.86 (d, J=8.0 Hz, 1H), 7.09(d, J=8.0 Hz, 1H), 7.50-7.59 (m, 2H), 7.84 (d, J=8.4 Hz, 1H), 8.27 (d,J=8.4 Hz, 1H).

Example 10.6-(5-hydroxypentyl)-1-isobutyl-3-methyl-7-((naphthalen-2-yloxy)methyl)pteridine-2,4(1H,3H)-dione

Follows Example 3 using the appropriate heteroaryl alcohol in theMitsunobu step. Step 4B product,5-(1-isobutyl-3-methyl-7-((naphthalen-2-yloxy)methyl)-2,4-dioxox-1,2,3,4-tetrahydropteridin-6-yl)pentylacetate:

Yellow solid. R_(f)=0.50 (Hex:EA=1:1); LC-MS (ESI): m/z 519 [M+1]⁺.

Step 5 (final) product6-(5-hydroxypentyl)-1-isobutyl-3-methyl-7-((naphthalene-2-yloxy)methyl)pteridine-2,4-(1H,3H)-dione(acetate removal conditions: K₂CO₃, MeOH, room temperature, 1 h): whitesolid. Single peak in analytical HPLC; LC-MS (ESI): m/z 477 [M+1]⁺.¹HNMR (400 MHz, CDCl₃) δ (ppm) 0.89 (d, J=6.4 Hz, 6H), 1.52-1.67 (m, 4H),1.88-1.94 (m, 2H), 2.18 (sep, J=6.4 Hz, 1H), 3.10 (t, J=7.6 Hz, 2H),3.55 (s, 3H), 3.69 (t, J=6.2 Hz, 2H), 4.13 (d, J=7.6 Hz, 2H), 5.45 (s,2H), 7.20-7.24 (m 2H), 7.37-7.50 (m, 2H), 7.71 (d, J=8.4 Hz, 1H), 7.80(d, J=8.8 Hz, 1H).

Example 11.7-((2-bromophenoxy)methyl)-6-(5-hydroxypentyl)-1-isobutyl-3-methylpteridine-2,4(1H,3H)-dione

Follows Example 3 using the appropriate heteroaryl alcohol in theMitsunobu step. Step 4B product,5-(7-((2-bromophenoxy)methyl)-1-isobutyl-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropteridin-6-yl)pentylacetate:

Colorless oil. R_(f)=0.50 (Hex:EA=1:1); LC-MS (ESI): m/z 547 [M+1]⁺.

Step 5 (final) product7-((2-bromophenoxy)methyl)-6-(5-hydroxypentyl)-1-isobutyl-3-methylpteridine-2,4-(1H,3H)-dione:white solid. >98% purity in analytical HPLC; LC-MS (ESI): m/z 505[M+1]⁺. ¹H NMR (400 MHz, CDCl₃) δ (ppm) 0.86 (d, J=6.8 Hz, 6H),1.48-1.69 (m, 4H), 1.83-1.95 (m, 2H), 2.09 (sep, J=6.8 Hz, 1H), 3.08 (t,J=7.6 Hz, 2H), 3.51 (s, 3H), 3.67 (t, J=6.2 Hz, 2H), 4.05 (d, J=7.6 Hz,2H), 5.40 (s, 2H), 6.87 (dt, J=1.2, 7.8 Hz, 1H), 6.92 (dd, J=1.2, 8.0Hz, 1H), 7.19-7.23 (m, 1H), 7.55 (dd, J=1.6, 8.0 Hz, 1H); ¹³C NMR (100MHz, CDCl₃) δ (ppm) 19.9, 25.5, 27.1, 28.1, 29.0, 32.3, 33.3, 49.3,62.3, 69.1, 112.1, 113.5, 122.8, 126.0, 128.4, 133.8, 145.7, 150.6,152.4, 152.6, 154.3, 160.2.

Example 12.6-(5-hydroxypentyl)-1-isobutyl-3-methyl-7-((quinolin-4-yloxy)methyl)pteridine-2,4(1H,3H)-dione

Follows Example 3 using the appropriate heteroaryl alcohol in theMitsunobu step. Step 4B product,5-(1-isobutyl-3-methyl-2,4-dioxo-7-((quinolin-4-yloxy)methyl)-1,2,3,4-tetrahydropteridin-6-yl)pentylacetate:

White solid. R_(f)=0.20 (EA); LC-MS (ESI): m/z 520 [M+1]⁺. ¹H NMR (400MHz, CDCl₃) δ (ppm) 0.63 (d, J=6.0 Hz, 6H), 1.40-1.50 (m, 2H), 1.55-1.64(m, 2H), 1.79-1.90 (m, 3H), 1.90 (s, 3H), 2.99 (s, 2H), 3.46 (s, 3H),3.85 (d, J=6.0 Hz, 2H), 3.98 (s, 2H), 5.76 (s, 2H), 7.30 (s, 1H),7.73-7.77 (m, 1H), 7.95-7.98 (m, 1H), 8.31 (d, J=8.0 Hz, 1H), 8.42 (d,J=8.8 Hz, 1H), 9.10 (s, 1H).

Step 5 (final) product6-(5-hydroxypentyl)-1-isobutyl-3-methyl-7-((quinolin-4-yloxy)methyl)pteridine-2,4(1H,3H)-dione(acetate removal conditions: K₂CO₃, MeOH, room temperature, 1 h): whitesolid (TFA salt). Single peak in analytical HPLC; LC-MS (ESI): m/z 478[M+1]⁺. ¹H NMR (400 MHz, CDCl₃) δ (ppm) 0.60 (d, J=6.8 Hz, 6H),1.40-1.60 (m, 4H), 1.80-1.89 (m, 2H), 1.92 (sep, J=6.8 Hz, 1H), 2.98 (s,2H), 3.44 (s, 3H), 3.58 (s, 2H), 3.83 (d, J=7.6 Hz, 2H), 5.79 (s, 2H),7.28 (s, 1H), 7.72-7.76 (m, 1H), 7.93-7.97 (m, 1H), 8.31-8.33 (m, 2H)9.08 (s, 1H).

Example 13.7-((2-chlorophenoxy)methyl)-6-(5-hydroxypentyl)-1-isobutyl-3-methylpteridine-2,4(1H,3H)-dione

Follows Example 3 using the appropriate heteroaryl alcohol in theMitsunobu step. Step 4B product,5-(7-((2-chlorophenoxy)methyl)-1-isobutyl-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropteridin-6-yl)pentylacetate:

Colorless oil. R_(f)=0.40 (Hex:EA=1:1); LC-MS (ESI): m/z 503 [M+1]⁺.

Step 5 (final) product7-((2-chlorophenoxy)methyl)-6-(5-hydroxypentyl)-1-isobutyl-3-methylpteridine-2,4-(1H,3H)-dione:white solid. >98% purity in analytical HPLC; LC-MS (ESI): m/z 461[M+1]⁺. ¹H NMR (400 MHz, CDCl₃) δ (ppm) 0.78 (d, J=6.8 Hz, 6H),1.40-1.60 (m, 4H), 1.75-1.90 (m, 2H), 2.00 (sep, J=6.8 Hz, 1H), 3.00 (t,J=7.6 Hz, 2H), 3.43 (s, 3H), 3.60 (t, J=5.8 Hz, 2H), 3.98 (d, J=7.6 Hz,2H), 5.32 (s, 2H), 6.83-6.88 (m, 2H), 7.06-7.11 (m, 1H), 7.29-7.32 (m,1H); ¹³C NMR (100 MHz, CDCl₃) δ (ppm) 19.9, 25.5, 27.1, 28.1, 29.0,32.3, 33.4, 49.3, 62.4, 69.1, 113.7, 122.4, 123.0, 126.0, 127.6, 130.7,145.7, 150.6, 152.4, 152.6, 153.4, 160.3.

Example 14.7-(([1,1′-biphenyl]-4-yloxy)methyl)-6-(5-hydroxypentyl)-1-isobutyl-3-methylpteridine-2,4(1H,3H)-dione

Follows Example 3 using the appropriate heteroaryl alcohol in theMitsunobu step. Step 4B product,5-(7-(([1,1′-biphenyl]-4-yloxy)methyl)-1-isobutyl-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropteridin-6-yl)pentylacetate:

Colorless oil. R_(f)=0.50 (Hex:EA=1:1); LC-MS (ESI): m/z 545 [M+1]⁺.

Step 5 (final) product7-(([1,1′-biphenyl]-4-yloxy)methyl)-6-(5-hydroxypentyl)-1-isobutyl-3-methylpteridine-2,4-(1H,3H)-dione:white solid. Single peak in analytical HPLC; LC-MS (ESI): m/z 503[M+1]⁺. ¹H NMR (400 MHz, CDCl₃) δ (ppm) 0.80 (d, J=6.8 Hz, 6H),1.40-1.60 (m, 4H), 1.78-1.90 (m, 2H), 2.07 (sep, J=6.8 Hz, 1H), 2.98 (t,J=7.6 Hz, 2H), 3.45 (s, 3H), 3.61 (t, J=6.4 Hz, 2H), 4.02 (d, J=7.6 Hz,2H), 5.27 (s, 2H), 6.95 (dd, J=2.0, 6.4 Hz, 2H), 7.22-7.26 (m, 1H),7.32-7.36 (m, 2H), 7.43-7.46 (m, 4H).

Example 15.6-(5-hydroxypentyl)-1-isobutyl-3-methyl-7-(phenoxymethyl)pteridine-2,4(1H,3H)-dione

Follows Example 3 using the appropriate heteroaryl alcohol in theMitsunobu step. Step 4B product,5-(1-isobutyl-3-methyl-2,4-dioxo-7-(phenoxymethyl)-1,2,3,4-tetrahydropteridin-6-yl)pentylacetate:

Colorless oil. R_(f)=0.30 (Hex:EA=1:1); LC-MS (ESI): m/z 469 [M+1]⁺.

Step 5 (final) product6-(5-hydroxypentyl)-1-isobutyl-3-methyl-7-(phenoxymethyl)pteridine-2,4-(1H,3H)-dione:white solid. Single peak in analytical HPLC; LC-MS (ESI): m/z 427[M+1]⁺.¹H NMR (400 MHz, CDCl₃) δ (ppm) 0.90 (d, J=6.8 Hz, 6H), 1.50-1.66(m, 4H), 1.88-1.96 (m, 2H), 2.16 (sep, J=6.4 Hz, 1H), 3.06 (t, J=7.6 Hz,2H), 3.54 (s, 3H), 3.69 (t, J=6.2 Hz, 2H), 4.11 (d, J=7.6 Hz, 2H), 5.32(s, 2H), 6.97-7.04 (m, 3H), 7.29-7.34 (m, 2H).

Example 16.6-(5-hydroxypentyl)-1-isobutyl-3-methyl-7-((3-(trifluoromethyl)phenoxy)methyl)pteridine-2,4(1H,3H)-dione

Follows Example 3 using the appropriate heteroaryl alcohol in theMitsunobu step. Step 4B product,5-(1-isobutyl-3-methyl-2,4-dioxo-7-((3-trifluoromethyl)phenoxy)methyl)-1,2,3,4-tetrahydropteridin-6-yl)pentylacetate:

Colorless oil. R_(f)=0.40 (Hex:EA=1:1); LC-MS (ESI): m/z 537 [M+1]⁺.

Step 5 (final) product6-(5-hydroxypentyl)-1-isobutyl-3-methyl-7-((3-(trifluoromethyl)phenoxy)methyl)pteridine-2,4-(1H,3H)-dione:white solid. >98% purity in analytical HPLC; LC-MS (ESI): m/z 495[M+1]⁺. ¹H NMR (400 MHz, CDCl₃) δ (ppm) 0.87 (d, J=6.8 Hz, 6H),1.50-1.70 (m, 4H), 1.83-1.95 (m, 2H), 2.14 (sep, J=6.8 Hz, 1H), 3.05 (t,J=7.6 Hz, 2H), 3.53 (s, 3H), 3.70 (t, J=5.8 Hz, 2H), 4.08 (d, J=7.6 Hz,2H), 5.37 (s, 2H), 7.14 (dd, J=2.4, 8.4 Hz, 1H), 7.23-7.29 (m, 2H), 7.43(t, J=8.0 Hz, 1H); ¹⁹F NMR (400 MHz, CDCl₃) δ (ppm) −62.7; ¹³C NMR (100MHz, CDCl₃) δ (ppm) 19.9, 25.5, 27.1, 28.2, 29.1, 32.2, 33.2, 49.3,62.4, 68.6, 111.4, 118.4, 122.4, 125.1, 126.2, 130.2, 131.9, 132.3,145.7, 150.6, 152.4, 158.1, 160.2.

Example 17.7-((2-fluorophenoxy)methyl)-6-(5-hydroxypentyl)-1-isobutyl-3-methylpteridine-2,4(1H,3H)-dione

Follows Example 3 using the appropriate heteroaryl alcohol in theMitsunobu step. Step 4B product,5-(7-((2-fluorophenoxy)methyl)-1-isobutyl-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropteridin-6-yl)pentylacetate:

Colorless oil. R_(f)=0.45 (Hex:EA=1:1); LC-MS (ESI): m/z 487 [M+1]⁺.

Step 5 (final) product7-((2-fluorophenoxy)methyl)-6-(5-hydroxypentyl)-1-isobutyl-3-methylpteridine-2,4-(1H,3H)-dione:white solid. >98% purity in analytical HPLC; LC-MS (ESI): m/z 445[M+1]⁺. ¹H NMR (400 MHz, CDCl₃) δ (ppm) 0.87 (d, J=6.8 Hz, 6H),1.49-1.69 (m, 4H), 1.85-1.95 (m, 2H), 2.11 (sep, J=6.8 Hz, 1H), 3.06 (t,J=7.6 Hz, 2H), 3.52 (s, 3H), 3.68 (t, J=5.8 Hz, 2H), 4.06 (d, J=7.6 Hz,2H), 5.38 (s, 2H), 6.94-7.13 (m, 4H); ¹⁹F NMR (400 MHz, CDCl₃) δ (ppm)−133.7; ¹³C NMR (100 MHz, CDCl₃) δ (ppm) 19.9, 25.5, 27.1, 28.3, 29.0,32.3, 33.3, 49.3, 62.4, 69.6, 115.5, 116.6, 122.3, 124.2, 126.0, 145.8,150.6, 151.5, 152.5, 152.8, 154.0, 160.3.

Example 18.6-(5-hydroxypentyl)-1-isobutyl-3-methyl-7-((quinolin-6-yloxy)methyl)pteridine-2,4(1H,3H)-dione

Follows Example 3 using the appropriate heteroaryl alcohol in theMitsunobu step. Step 4B product,5-(1-isobutyl-3-methyl-2,4-dioxo-7-((quinolin-6-yloxy)methyl)-1,2,3,4-tetrahydropteridin-6-yl)pentylacetate:

Yellow solid. R_(f)=0.15 (Hex:EA=1:1); LC-MS (ESI): m/z 520 [M+1]⁺.

Step 5 (final) product6-(5-hydroxypentyl)-1-isobutyl-3-methyl-7-((quinolin-6-yloxy)methyl)pteridine-2,4-(1H,3H)-dione(acetate removal conditions: K₂CO₃, MeOH, room temperature, 1 h): yellowsolid (TFA salt). Single peak in analytical HPLC; LC-MS (ESI): m/z 478[M+1]⁺. ¹H NMR (400 MHz, CDCl₃) δ (ppm) 0.80 (d, J=6.8 Hz, 6H),1.44-1.57 (m, 4H), 1.80-1.90 (m, 2H), 2.08 (sep, J=6.4 Hz, 1H), 2.98 (t,J=7.4 Hz, 2H), 3.45 (s, 3H), 3.62 (t, J=6.2 Hz, 2H), 4.01 (d, J=7.6 Hz,2H), 5.42 (s, 2H), 7.31-7.33 (m, 1H), 7.65-7.77 (m, 2H), 8.45 (d, J=9.2Hz, 1H), 8.52 (d, J=8.4 Hz, 1H), 9.02 (d, J=8.4 Hz, 1H).

Example 19.7-((2,4-dibromophenoxy)methyl)-6-(5-hydroxypentyl)-1-isobutyl-3-methylpteridine-2,4(1H,3H)-dione

Follows Example 3 using the appropriate heteroaryl alcohol in theMitsunobu step. Step 4B product,5-(7-((2,4-dibromophenoxy)methyl)-1-isobutyl-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropteridin-6-yl)pentylacetate:

Colorless oil. R_(f)=0.40 (Hex:EA=1:1); LC-MS (ESI): m/z 625 [M+1]⁺.

Step 5 (final) product7-((2,4-dibromophenoxy)methyl)-6-(5-hydroxypentyl)-1-isobutyl-3-methylpteridine-2,4-(1H,3H)-dione:white solid. Single peak in analytical HPLC; LC-MS (ESI): m/z 583[M+1]⁺. ¹H NMR (400 MHz, CDCl₃) δ (ppm) 0.79 (d, J=6.8 Hz, 6H),1.40-1.671 (m, 4H), 1.75-1.86 (m, 2H), 2.04 (sep, J=6.8 Hz, 1H), 2.98(t, J=7.86 Hz, 2H), 3.45 (s, 3H), 3.61 (t, J=6.2 Hz, 2H), 3.98 (d, J=7.2Hz, 2H), 5.29 (s, 2H), 6.73 (d, J=8.8 Hz, 1H), 7.24 (dd, J=2.4, 8.8 Hz,1H), 7.62 (d, J=2.4 Hz, 1H).

Example 20.6-(5-hydroxypentyl)-1-isobutyl-3-methyl-7-((quinolin-7-yloxy)methyl)pteridine-2,4(1H,3H)-dione

Follows Example 3 using the appropriate heteroaryl alcohol in theMitsunobu step. Step 4B product,5-(1-isobutyl-3-methyl-2,4-dioxo-7-((quinolin-7-yloxy)methyl)-1,2,3,4-tetrahydropteridin-6-yl)pentylacetate:

Yellow solid. R_(f)=0.10 (Hex:EA=1:1); LC-MS (ESI): m/z 520 [M+1]⁺.

Step 5 (final) product6-(5-hydroxypentyl)-1-isobutyl-3-methyl-7-((quinolin-7-yloxy)methyl)pteridine-2,4-(1H,3H)-dione:white solid (TFA salt). >95% purity in analytical HPLC; LC-MS (ESI): m/z478 [M+1]⁺. ¹H NMR (400 MHz, CDCl₃) δ (ppm) 0.85 (d, J=6.8 Hz, 6H),1.51-1.67 (m, 4H), 1.90-1.98 (m, 2H), 2.15 (sep, J=6.4 Hz, 1H), 3.08 (t,J=7.6 Hz, 2H), 3.56 (s, 3H), 3.72 (t, J=6.4 Hz, 2H), 4.07 (d, J=7.6 Hz,2H), 5.63 (s, 2H), 7.54-7.58 (m, 1H), 7.71-7.75 (m, 1H), 8.04 (d, J=9.2Hz, 1H), 8.26 (d, J=2.0 Hz, 1H), 8.70 (d, J=8.0 Hz, 1H), 9.10 (d, J=5.6Hz, 1H).

Example 21.7-((2-bromo-4-chlorophenoxy)methyl)-6-(5-hydroxypentyl)-1-isobutyl-3-methylpteridine-2,4(1H,3H)-dione

Follows Example 3 using the appropriate heteroaryl alcohol in theMitsunobu step. Step 4B product,5-(7-((2-bromo-4-chlorophenoxy)methyl)-1-isobutyl-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropteridin-6-yl)pentylacetate:

Colorless oil. R_(f)=0.40 (Hex:EA=1:1); LC-MS (ESI): m/z 581 [M+1]⁺.

Step 5 (final) product,7-((2-bromo-4-chlorophenoxy)methyl)-6-(5-hydroxypentyl)-1-isobutyl-3-methylpteridine-2,4-(1H,3H)-dione:white solid. Single peak in analytical HPLC; LC-MS (ESI): m/z 539[M+1]⁺. ¹H NMR (400 MHz, CDCl₃) δ (ppm) 0.89 (d, J=6.8 Hz, 6H),1.50-1.71 (m, 4H), 1.85-1.95 (m, 2H), 2.09 (sep, J=6.8 Hz, 1H), 3.09 (t,J=7.6 Hz, 2H), 3.52 (s, 3H), 3.71 (t, J=6.2 Hz, 2H), 4.09 (d, J=7.6 Hz,2H), 5.39 (s, 2H), 6.88 (d, J=8.8 Hz, 1H), 7.21 (dd, J=2.4, 8.8 Hz, 1H),7.59 (d, J=2.4 Hz, 1H).

Example 22.6-(5-hydroxypentyl)-1-isobutyl-3-methyl-7-((4-(trifluoromethyl)phenoxy)methyl)pteridine-2,4(1H,3H)-dione

Follows Example 3 using the appropriate heteroaryl alcohol in theMitsunobu step. Step 4B product,5-(1-isobutyl-3-methyl-2,4-dioxo-7-((4-trifluoromethyl)phenoxy)methyl)-1,2,3,4-tetrahydropteridin-6-yl)pentylacetate:

Colorless oil. R_(f)=0.40 (Hex:EA=1:1); LC-MS (ESI): m/z 537 [M+1]⁺.

Step 5 (final) product6-(5-hydroxypentyl)-1-isobutyl-3-methyl-7-((4-(trifluoromethyl)phenoxy)methyl)pteridine-2,4-(1H,3H)-dione:white solid. >98% purity in analytical HPLC; LC-MS (ESI): m/z 495[M+1]⁺. ¹H NMR (400 MHz, CDCl₃) δ (ppm) 0.77 (d, J=6.8 Hz, 6H),1.40-1.60 (m, 4H), 1.80-1.90 (m, 2H), 1.98 (sep, J=6.8 Hz, 1H), 2.98 (t,J=7.4 Hz, 2H), 3.44 (s, 3H), 3.60 (t, J=5.6 Hz, 2H), 3.97 (d, J=7.2 Hz,2H), 5.29 (s, 2H), 6.95 (d, J=8.4 Hz, 2H), 7.47 (d, J=8.4 Hz, 2H); ¹⁹FNMR (400 MHz, CDCl₃) δ (ppm) −61.7; ¹³C NMR (100 MHz, CDCl₃) δ (ppm)19.9, 25.5, 27.1, 28.2, 29.1, 32.2, 33.2, 49.3, 62.4, 68.4, 114.7,120.1, 122.8, 123.9, 125.5, 126.1, 127.0, 127.1, 128.2, 145.7, 150.6,152.3, 160.2.

Example 23.7-(([1,1′-biphenyl]-2-yloxy)methyl)-6-(5-hydroxypentyl)-1-isobutyl-3-methylpteridine-2,4(1H,3H)-dione

Follows Example 3 using the appropriate heteroaryl alcohol in theMitsunobu step. Step 4B product,5-(7-(([1,1′-biphenyl]-2-yloxy)methyl)-1-isobutyl-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropteridin-6-yl)pentylacetate:

Colorless oil. R_(f)=0.50 (Hex:EA=1:1); LC-MS (ESI): m/z 545 [M+1]⁺.

Step 5 (final) product,7-(([1,1′-biphenyl]-2-yloxy)methyl)-6-(5-hydroxypentyl)-1-isobutyl-3-methylpteridine-2,4-(1H,3H)-dione:white solid. Single peak in analytical HPLC; LC-MS (ESI): m/z 503[M+1]⁺. ¹H NMR (400 MHz, CDCl₃) δ (ppm) 0.75 (d, J=6.8 Hz, 6H),1.25-1.31 (m, 2H), 1.41-1.46 (m, 2H), 1.57-1.63 (m, 2H), 1.97 (sep,J=6.8 Hz, 1H), 2.77 (t, J=7.4 Hz, 2H), 3.43 (s, 3H), 3.56 (t, J=5.8 Hz,2H), 3.98 (d, J=7.2 Hz, 2H), 5.19 (s, 2H), 6.91-7.00 (m, 2H), 7.16-7.28(m, 5H), 7.38-7.41 (m, 2H); ¹³C NMR (100 MHz, CDCl₃) δ (ppm) 19.9, 25.3,27.1, 27.8, 29.0, 32.2, 33.0, 49.2, 62.4, 69.2, 113.4, 122.2, 125.8,127.1, 128.0, 128.5, 129.4, 131.3, 131.5, 138.1, 145.6, 150.7, 152.4,153.3, 154.8, 160.3.

Example 24.7-((2-bromo-5-fluorophenoxy)methyl)-6-(5-hydroxypentyl)-1-isobutyl-3-methylpteridine-2,4(1H,3H)-dione

Follows Example 3 using the appropriate heteroaryl alcohol in theMitsunobu step. Step 4B product,5-(7-((2-bromo-5-fluorophenoxy)methyl)-1-isobutyl-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropteridin-6-yl)pentylacetate:

Colorless oil. R_(f)=0.45 (Hex:EA=1:1); LC-MS (ESI): m/z 565 [M+1]⁺.

Step 5 (final) product,7-((2-bromo-5-fluorophenoxy)methyl)-6-(5-hydroxypentyl)-1-isobutyl-3-methylpteridine-2,4-(1H,3H)-dione:white solid. Single peak in analytical HPLC; LC-MS (ESI): m/z 523[M+1]⁺. ¹H NMR (400 MHz, CDCl₃) δ (ppm) 0.70 (d, J=6.8 Hz, 6H),1.40-1.61 (m, 4H), 1.75-1.90 (m, 2H), 2.07 (sep, J=6.8 Hz, 1H), 3.00 (t,J=7.6 Hz, 2H), 3.44 (s, 3H), 3.60 (t, J=5.8 Hz, 2H), 4.00 (d, J=7.2 Hz,2H), 5.30 (s, 2H), 6.53-6.57 (m, 1H), 6.64-6.67 (m, 1H), 7.41-7.44 (m,1H); ¹⁹F NMR (400 MHz, CDCl₃) δ (ppm) −111.3; ¹³C NMR (100 MHz, CDCl₃) δ(ppm) 19.9, 25.5, 27.1, 28.1, 29.1, 32.3, 33.3, 49.4, 62.4, 69.3, 101.9,106.3, 109.4, 126.3, 134.0, 145.7, 150.6, 152.0, 155.2, 160.1, 161.2,163.7.

Example 25.6-(5-hydroxypentyl)-1-isobutyl-7-((isoquinolin-8-yloxy)methyl)-3-methylpteridine-2,4(1H,3H)-dione

Follows Example 3 using the appropriate heteroaryl alcohol in theMitsunobu step. Step 4B product,5-(1-isobutyl-7-((isoquinolin-8-yloxy)methyl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropteridin-6-yl)pentylacetate:

Yellow solid. R_(f)=0.10 (Hex:EA=1:1); LC-MS (ESI): m/z 520 [M+1]⁺.

Step 5 (final) product,6-(5-hydroxypentyl-1-isobutyl-7-((isoquinolin-8-yloxy)methyl)-3-methyl-pteridine-2,4-(1H,3H)-dione:white solid (TFA salt). Single peak in analytical HPLC; LC-MS (ESI): m/z478 [M+1]⁺. ¹H NMR (400 MHz, CD₃OD) δ (ppm) 0.45 (d, J=6.8 Hz, 6H),1.42-1.55 (m, 4H), 1.60-1.81 (m, 3H), 2.97 (t, J=7.8 Hz, 2H), 3.35 (s,3H), 3.45 (t, J=6.4 Hz, 2H), 3.72 (d, J=7.6 Hz, 2H), 5.82 (s, 2H), 7.39(d, J=8.0 Hz, 1H), 7.76 (d, J=8.0 Hz, 1H), 8.02 (t, J=8.0 Hz, 1H), 8.34(s, 1H), 8.50 (s, 1H), 9.82 (s, 1H).

Example 26.6-(5-hydroxypentyl)-1-isobutyl-3-methyl-7-((quinolin-8-yloxy)methyl)pteridine-2,4(1H,3H)-dione

Follows Example 3 using the appropriate heteroaryl alcohol in theMitsunobu step. Step 4B product,5-(1-isobutyl-3-methyl-2,4-dioxo-7-((quinolin-8-yloxy)methyl)-1,2,3,4-tetrahydropteridin-6-yl)pentylacetate:

Yellow solid. R_(f)=0.15 (EA); LC-MS (ESI): m/z 520 [M+1]⁺.

Step 5 (final) product,6-(5-hydroxypentyl-1-isobutyl-3-methyl-7-((quinolin-8-yloxy)methyl)pteridine-2,4-(1H,3H)-dione(acetate removal conditions: K₂CO₃, MeOH, room temperature, 1 h): whitesolid (TFA salt). Single peak in analytical HPLC; LC-MS (ESI): m/z 478[M+1]⁺. ¹H NMR (400 MHz, CDCl₃) δ (ppm) 0.68 (d, J=6.8 Hz, 6H),1.39-1.50 (m, 4H), 1.70-1.83 (m, 2H), 1.99 (sep, J=6.8 Hz, 1H), 3.06 (t,J=7.2 Hz, 2H), 3.44 (s, 3H), 3.54 (s, 2H), 3.94 (d, J=7.2 Hz, 2H), 5.57(s, 2H), 7.24 (d, J=6.8 Hz, 1H), 7.46-7.52 (m, 2H), 7.66 (d, J=8.0 Hz,1H), 8.44 (d, J=8.0 Hz, 1H), 9.20 (s, 1H).

Example 27.6-(5-hydroxypentyl)-1-isobutyl-7-((isoquinolin-3-yloxy)methyl)-3-methylpteridine-2,4(1H,3H)-dione

Follows Example 3 using the appropriate heteroaryl alcohol in theMitsunobu step. Step 4B product,5-(1-isobutyl-7-((isoquinolin-3-yloxy)methyl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropteridin-6-yl)pentylacetate:

Yellow solid. R_(f)=0.15 (Hex:EA=1:1); LC-MS (ESI): m/z 520 [M+1]⁺.

Step 5 (final) product,6-(5-hydroxypentyl)-1-isobutyl-7-((isoquinolin-3-yloxy)methyl)-3-methylpteridine-2,4-(1H,3H)-dione(acetate removal conditions: K₂CO₃, MeOH, room temperature, 1 h): yellowsolid (TFA salt). Single peak in analytical HPLC; LC-MS (ESI): m/z 478[M+1]⁺. ¹H NMR (400 MHz, MeOD-d₄) δ (ppm) 0.40 (d, J=6.8 Hz, 6H),1.40-1.62 (m, 4H), 1.75-1.90 (m, 3H), 2.94 (t, J=7.6 Hz, 2H), 3.32 (s,3H), 3.48 (t, J=6.4 Hz, 2H), 3.71 (d, J=7.6 Hz, 2H), 5.74 (s, 2H), 7.17(s, 1H), 7.30-7.35 (m, 1H), 7.52-7.56 (m, 1H), 7.68 (d, J=8.4 Hz, 1H),7.84 (d, J=8.4 Hz, 1H), 8.77 (s, 1H).

Example 28.6-(5-hydroxypentyl)-1-isobutyl-3-methyl-7-((pyridin-4-yloxy)methyl)pteridine-2,4(1H,3H)-dione

Follows Example 3 using the appropriate heteroaryl alcohol in theMitsunobu step. Step 4B product,5-(1-isobutyl-3-methyl-2,4-dioxo-7-((pyridin-4-yloxy)methyl)-1,2,3,4-tetrahydropteridin-6-yl)pentylacetate:

Yellow solid. R_(f)=0.15 (Hex:EA=1:1); LC-MS (ESI): m/z 470 [M+1]⁺.

Step 5 (final) product,6-(5-hydroxypentyl-1-isobutyl-3-methyl-7-((pyridin-4-yloxy)methyl)pteridine-2,4-(1H,3H)-dione:white solid (TFA salt). Single peak in analytical HPLC; LC-MS (ESI): m/z428 [M+1]⁺. ¹H NMR (400 MHz, CD₃OD) δ (ppm) 0.67 (d, J=6.8 Hz, 6H),1.40-1.53 (m, 4H), 1.75-1.91 (m, 3H), 2.90 (t, J=7.8 Hz, 2H), 3.36 (s,3H), 3.48 (t, J=6.4 Hz, 2H), 3.79 (d, J=7.2 Hz, 2H), 5.81 (s, 2H), 7.57(d, J=6.0 Hz, 2H), 8.63 (d, J=6.0 Hz, 2H).

Example 29.7-(((6,8-dibromoisoquinolin-5-yl)oxy)methyl)-6-(5-hydroxypentyl)-1-isobutyl-3-methylpteridine-2,4(1H,3H)-dione

Follows Example 3 using the appropriate heteroaryl alcohol in theMitsunobu step. Step 4B product,5-(7-(((6,8-dibromoisoquinolin-5-yl)oxy)methyl)-1-isobutyl-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropteridin-6-yl)pentylacetate:

Yellow solid. R_(f)=0.20 (Hex:EA=1:1); LC-MS (ESI): m/z 676 [M+1]⁺.

Step 5 (final) product,7-(((6,8-dibromoisoquinolin-5-yl)oxy)methyl)-6-(5-hydroxypentyl-1-isobutyl-3-methylpteridine-2,4-(1H,3H)-dione:white solid (TFA salt). Single peak in analytical HPLC; LC-MS (ESI): m/z634 [M+1]⁺. ¹H NMR (400 MHz, CD₃OD) δ (ppm) 0.64 (d, J=6.8 Hz, 6H),1.45-1.63 (m, 5H), 1.80-1.90 (m, 2H), 3.16 (t, J=7.8 Hz, 2H), 3.37 (s,3H), 3.49 (t, J=6.2 Hz, 2H), 3.79 (d, J=7.6 Hz, 2H), 5.40 (s, 2H), 7.86(s, 1H), 8.09 (s, 1H), 8.55 (s, 1H).

Example 30.6-(5-hydroxypentyl)-1-isobutyl-3-methyl-7-((quinoxalin-5-yloxy)methyl)pteridine-2,4(1H,3H)-dione

Follows Example 3 using the appropriate heteroaryl alcohol in theMitsunobu step. Step 4B product,5-(1-isobutyl-3-methyl-2,4-dioxo-7-((quinoxalin-5-yloxy)methyl)-1,2,3,4-tetrahydropteridin-6-yl)pentylacetate:

Yellow solid. R_(f)=0.15 (Hex:EA=1:1); LC-MS (ESI): m/z 521 [M+1]⁺.

Step 5 (final) product,6-(5-hydroxypentyl-1-isobutyl-3-methyl-7-((quinoxalin-5-yloxy)methyl)pteridine-2,4-(1H,3H)-dione:white solid (TFA salt). Single peak in analytical HPLC; LC-MS (ESI): m/z479 [M+1]⁺. ¹H NMR (400 MHz, CD₃OD) δ (ppm) 0.43 (d, J=6.8 Hz, 6H),1.38-1.46 (m, 4H), 1.74-1.83 (m, 3H), 2.97 (t, J=7.8 Hz, 2H), 3.34 (s,3H), 3.43 (t, J=6.4 Hz, 2H), 3.72 (d, J=7.6 Hz, 2H), 5.69 (s, 2H), 7.21(dd, J=2.0, 6.8 Hz, 1H), 7.59-7.63 (m, 2H), 8.77 (d, J=2.0 Hz, 1H), 8.84(d, J=2.0 Hz, 1H).

Example 31.6-(5-hydroxypentyl)-1-isobutyl-3-methyl-7-((pyridin-3-yloxy)methyl)pteridine-2,4(1H,3H)-dione

Follows Example 3 using the appropriate heteroaryl alcohol in theMitsunobu step. Step 4B product,5-(1-isobutyl-3-methyl-2,4-dioxo-7-((pyridine-3-yloxy)methyl)-1,2,3,4-tetrahydropteridin-6-yl)pentylacetate:

Colorless oil. R_(f)=0.15 (Hex:EA=1:1); LC-MS (ESI): m/z 470 [M+1]⁺.

Step 5 (final) product,6-(5-hydroxypentyl)-1-isobutyl-3-methyl-7-((pyridine-3-yloxy)methyl)pteridine-2,4-(1H,3H)-dione:white solid (TFA salt). Single peak in analytical HPLC; LC-MS (ESI): m/z428 [M+1]⁺. ¹H NMR (400 MHz, CDCl₃) δ (ppm) 0.80 (d, J=6.8 Hz, 6H),1.50-1.71 (m, 4H), 1.80-1.91 (m, 2H), 2.02 (sep, J=6.8 Hz, 1H), 3.03 (t,J=7.8 Hz, 2H), 3.48 (s, 3H), 3.60 (t, J=6.2 Hz, 2H), 3.95 (d, J=7.2 Hz,2H), 5.76 (s, 2H), 8.00 (s, 1H), 8.19-8.22 (m, 1H), 8.61 (br s, 2H).

Example 32.6-(5-hydroxypentyl)-1-isobutyl-3-methyl-7-((3-nitrophenoxy)methyl)pteridine-2,4(1H,3H)-dione

Follows Example 3 using the appropriate heteroaryl alcohol in theMitsunobu step. Step 4B product,5-(1-isobutyl-3-methyl-7-((3-nitrophenoxy)methyl)-2,4-dioxo-1,2,3,4-tetrahydropteridin-6-yl)pentylacetate:

Colorless oil. R_(f)=0.30 (Hex:EA=1:1); LC-MS (ESI): m/z 514 [M+1]⁺.

Step 5 (final) product,6-(5-hydroxypentyl)-1-isobutyl-3-methyl-7-((3-nitrophenoxy)methyl)pteridine-2,4-(1H,3H)-dione:yellow solid. Single peak in analytical HPLC; LC-MS (ESI): m/z 472[M+1]⁺. ¹H NMR (400 MHz, CDCl₃) δ (ppm) 0.80 (d, J=6.8 Hz, 6H),1.40-1.62 (m, 4H), 1.82-1.90 (m, 2H), 2.07 (sep, J=6.8 Hz, 1H), 2.97 (t,J=7.0 Hz, 2H), 3.45 (s, 3H), 3.62 (t, J=6.2 Hz, 2H), 4.01 (d, J=7.2 Hz,2H), 5.32 (s, 2H), 7.21-7.24 (m, 1H), 7.37-7.41 (m, 1H), 7.78-7.82 (m,2H).

Example 33.7-((3-aminophenoxy)methyl)-6-(5-hydroxypentyl)-1-isobutyl-3-methylpteridine-2,4(1H,3H)-dione

Prepared from the product of Example 32 by catalytic hydrogenation usingPd/C. Data: yellow solid (TFA salt). Single peak in analytical HPLC;LC-MS (ESI): m/z 442 [M+1]⁺. ¹H NMR (400 MHz, CDCl₃) δ (ppm) 0.80 (d,J=6.8 Hz, 6H), 1.30-1.52 (m, 4H), 1.65-1.80 (m, 2H), 2.06 (sep, J=6.8Hz, 1H), 2.87 (t, J=7.0 Hz, 2H), 3.42 (s, 3H), 3.55 (t, J=6.2 Hz, 2H),4.00 (d, J=7.2 Hz, 2H), 5.22 (s, 2H), 6.61-6.69 (m, 3H), 7.12-7.16 (m,1H).

Example 34.2-((6-(5-hydroxypentyl)-1-isobutyl-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropteridin-7-yl)methoxy)benzonitrile

Follows Example 3 using the appropriate heteroaryl alcohol in theMitsunobu step. Step 4B product,5-(7-((2-cyanophenoxy)methyl)-1-isobutyl-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropteridin-6-yl)pentylacetate:

Colorless oil. R_(f)=0.15 (Hex:EA=1:1); LC-MS (ESI): m/z 494 [M+1]⁺.

Step 5 (final) product,2-((6-(5-hydroxypentyl)-1-isobutyl-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropteridine-7-yl)methoxy)benzonitrile:orange solid. Single peak in analytical HPLC; LC-MS (ESI): m/z 452[M+1]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm) 0.88 (d, J=6.8 Hz, 6H),1.40-1.69 (m, 6H), 2.18 (sep, J=6.8 Hz, 1H), 3.20 (t, J=7.8 Hz, 2H),3.33 (s, 3H), 3.45 (t, J=6.4 Hz, 2H), 3.97 (d, J=7.6 Hz, 2H), 4.32 (t,J=5.2 Hz, 1H), 7.08 (s, 2H), 7.22-7.27 (m, 1H), 7.44-7.47 (m, 2H), 7.91(d, J=7.6 Hz, 1H).

Certain compounds of the invention were made using the product ofExample 1 as the starting material and following the procedures ofGeneral Scheme 3:

The following compounds were made according to the methods of GeneralScheme 3:

TABLE 2 35

B R¹ = Me, R² = i-Bu, R⁴ = H, Z = CH₂, n = 1, E = CH₂, J = O,  

  ring = phenyl, R⁵ = H

Example 35.6-(2-(hydroxymethyl)phenethyl)-1-isobutyl-3-methyl-7-((naphthalen-1-yloxy)methyl)pteridine-2,4(1H,3H)-dione

Step 1

2-((7-(((tert-butyldimethylsilyl)oxy)methyl)-1-isobutyl-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropteridin-6-yl)ethynyl)benzylacetate: A mixture of7-(((tert-butyldimethylsilyl)oxy)methyl)-1-isobutyl-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropteridin-6-yltrifluoromethanesulfonate (1.37 g, 2.61 mmol), 2-ethynylbenzyl acetate(0.591 g, 3.39 mmol), and CuI (75 mg, 0.39 mmol) in DMF (39 mL) wasdegassed. Pd(PPh₃)₄ (151 mg, 0.13 mmol) was added followed by TEA (1.58g, 15.7 mmol), and degassed. The reaction was stirred at 100° C. for 1hour, then cooled to room temperature. The reaction was quenched withsaturated NH₄Cl, extracted with EA. The combined organic extracts werewashed with brine, dried over Na₂SO₄. The solvent was removed and theresidue was purified by column (Hex:EA=3:1) to afford 1.31 g (91%) of2-((7-(((tert-butyldimethylsilyl)oxy)methyl)-1-isobutyl-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropteridin-6-yl)ethynyl)benzylacetate as a yellow solid. R_(f)=0.65 (Hex:EA=1:1); LC-MS (ESI): m/z 551[M+1]⁺. ¹H NMR (400 MHz, CDCl₃) δ (ppm) 0.17 (s, 6H), 0.97 (s, 9H), 1.02(d, J=6.0 Hz, 6H), 2.15 (s, 3H), 2.32 (hep, J=6.4 Hz, 1H), 3.56 (s, 3H),4.26 (d, J=7.6 Hz, 2H), 5.17 (s, 2H), 5.40 (s, 2H), 7.24-7.69 (m, 4H).

Steps 2 and 3

2-(2-(7-(hydroxymethyl)-1-isobutyl-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropteridin-6-yl)ethyl)benzylacetate: A solution of2-((7-(((tert-butyldimethylsilyl)oxy)methyl)-1-isobutyl-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropteridin-6-yl)ethynyl)benzylacetate (1.19 g, 2.16 mmol) in THF (65 mL) was treated with a solutionof TsOH (0.41 g, 2.16 mmol) in H₂O (13 mL). The reaction was stirred atroom temperature for 24 hours. The reaction was diluted with EA, washedwith brine, dried over Na₂SO₄. The solvent was removed and the residuewas purified by column (Hex:EA=1:1) to afford2-((7-(hydroxymethyl)-1-isobutyl-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropteridin-6-yl)ethynyl)benzylacetate as a yellow solid, which was used directly for the next step.R_(f)=0.25 (Hex:EA=1:1); LC-MS (ESI): m/z 437 [M+1]⁺. A solution of2-(2-(7-(hydroxymethyl)-1-isobutyl-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropteridin-6-yl)ethyl)benzylacetate in MeOH (100 mL) and THF (20 mL) was treated with Pd/C (160 mg,10% on charcoal) and stirred under atmosphere of H₂ for 1 h. Thereaction was filtered and concentrated. The crude product was purifiedby column (Hex:EA=1:1) to afford 293 mg (31% for two steps) of2-((7-(((tert-butyldimethylsilyl)oxy)methyl)-1-isobutyl-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropteridin-6-yl)ethynyl)benzylacetate as a white solid. R_(f)=0.20 (Hex:EA=1:1); LC-MS (ESI): m/z 441[M+1]⁺. ¹H NMR (400 MHz, CDCl₃) δ (ppm) 0.96 (d, J=6.8 Hz, 6H), 2.11 (s,3H), 2.24 (hep, J=6.4 Hz, 1H), 3.16-3.20 (m, 4H), 3.56 (s, 3H), 4.18 (d,J=7.6 Hz, 2H), 4.67 (s, 2H), 5.18 (s, 2H), 7.10-7.37 (m, 4H).

Step 4

2-(2-(1-isobutyl-3-methyl-7-((naphthalen-1-yloxy)methyl)-2,4-dioxo-1,2,3,4-tetrahydropteridin-6-yl)ethyl)benzylacetate: A mixture of2-((7-(((tert-butyldimethylsilyl)oxy)methyl)-1-isobutyl-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropteridin-6-yl)ethynyl)benzylacetate (44 mg, 0.10 mmol), naphthalen-1-ol (22 mg, 0.15 mmol), and PPh₃(39 mg, 0.15 mmol) in THF (4 mL) was treated with DIAD (30 mg, 0.15mmol). The reaction was stirred at room temperature for 24 hours. Thereaction was diluted with EA, washed with brine, dried over Na₂SO₄. Thesolvent was removed and the residue was purified by column (Hex:EA=3:1)to afford 35 mg (62%) of2-(2-(1-isobutyl-3-methyl-7-((naphthalen-1-yloxy)methyl)-2,4-dioxo-1,2,3,4-tetrahydropteridin-6-yl)ethyl)benzylacetate as a yellow oil. R_(f)=0.45 (Hex:EA=1:1); LC-MS (ESI): m/z 567[M+1]⁺. ¹H NMR (400 MHz, CDCl₃) δ (ppm) 0.77 (d, J=6.4 Hz, 6H), 2.00 (s,3H), 2.08 (hep, J=6.4 Hz, 1H), 3.27 (t, J=7.4 Hz, 2H), 3.44 (t, J=7.4Hz, 2H), 3.58 (s, 3H), 4.03 (d, J=7.6 Hz, 2H), 5.12 (s, 2H), 5.21 (s,2H), 6.65 (d, J=7.1 Hz, 1H), 7.06 (dd, J=1.6, 6.8 Hz, 1H), 7.20-7.52 (m,7H), 7.81 (d, J=8.0 Hz, 1H), 8.21 (d, J=8.4 Hz, 1H).

Step 5

6-(2-(hydroxymethyl)phenethyl)-1-isobutyl-3-methyl-7-((naphthalen-1-yloxy)methyl)pteridine-2,4(1H,3H)-dione:A solution of2-(2-(1-isobutyl-3-methyl-7-((naphthalen-1-yloxy)methyl)-2,4-dioxo-1,2,3,4-tetrahydropteridin-6-yl)ethyl)benzylacetate (35 mg, 0.062 mmol) in EtOH (10 mL, 95%) was treated with KCN(45 mg). The reaction was stirred at room temperature for 24 h. Thereaction was concentrated and purified by preparative HPLC to afford 25mg (77%) of6-(2-(hydroxymethyl)phenethyl)-1-isobutyl-3-methyl-7-((naphthalen-1-yloxy)methyl)pteridine-2,4(1H,3H)-dioneas a white solid. LC-MS (ESI): m/z 525 [M+1]⁺. ¹H NMR (400 MHz, CDCl₃) δ(ppm) 0.79 (d, J=6.8 Hz, 6H), 2.10 (hep, J=6.4 Hz, 1H), 3.32 (t, J=6.8Hz, 2H), 3.50 (t, J=6.8 Hz, 2H), 3.54 (s, 3H), 4.05 (d, J=7.6 Hz, 2H),4.75 (s, 2H), 5.36 (s, 2H), 6.75 (d, J=7.6 Hz, 1H), 7.11-7.55 (m, 8H),7.83 (d, J=7.6 Hz, 1H), 8.24 (d, J=8.0 Hz, 1H).

Biological Activity Example 36. Biological Activity of SelectedCompounds of the Invention

Specific Examples of compounds of the invention, with estimated EC₅₀values determined using an MTT assay for 4-day viability of Raji(Burkitt's) lymphoma cells, a cell line known to highly express MCT1 andto be sensitive to small molecule MCT inhibitors,⁴ are shown in Table 3.Assay protocols follow those described in the literature.⁴ Other assaysthat are not described here but that are standard in the field, such asan assay for competitive inhibition of transport of radiolabeled lacticacid, an MCT substrate, may also be useful in establishing mechanism ofaction of these compounds.

TABLE 3 approximate Example potency (EC₅₀ nM) 2 <50 3 <50 4 <50 5 <50 6<50 7 <50 8 300 9 <50 10 <50 11 <50 12 <50 13 <50 14 ≦100 15 ≦100 16≦100 17 ≦100 18 ≦100 19 ≦250 20 ≦250 21 ≦250 22 ≦250 23 ≦250 24 ≦250 25≦250 26 ≦500 27 ≦500 28 ≦1000 29 ≦1000 30 ≦1000 31 ≦1000 32 ≦1000 33≦100 34 ≧2000 35 ≦100

Example 37. Mouse Xenograft Studies

The in vivo effects of a few selected agents have been evaluated inmouse xenograft models and found to be effective. Protocols follow thosedescribed in the literature.⁴

Mice were transplanted with cultured tumor cells and after an incubationperiod (typically 8-12 days), mice were left untreated or were treateddaily with a 30 mg/kg dose of the test compound. Tumor volumes weremeasured with calipers over ˜20 days of treatment. Tumors were excisedand weighed at the end of treatment. In some experiments the mice wereco-treated daily with a 30 mg/kg dose of the test compound and 5 mg/kgof metformin.

In a xenograft experiment using T47D tumor cells, and estrogenreceptor-positive breast cancer cell line that also selectively expressMCT1⁴, and test compound SR-11431 (the product of Example 3, FIG. 3)there was a significant reduction of tumor volume (FIG. 4). Acorresponding reduction in final tumor mass (FIG. 5) was also observedversus vehicle treated transplanted animals.

In a separate experiment, this same compound was used in a study usingimplanted tumors derived from Raji Burkitt lymphoma cells, implantedinto nude mice and treated as before with vehicle, with SR-11431, orwith SR-11431 plus metformin. Reduction of tumor volume over time (FIG.6) was observed for both SR-11431-treated and(SR-11431+metformin)-treated animals. The (SR-11431+metformin)-treatedcohort of animals showed a profound regression of tumor volume over the30-day time course (triangles, FIG. 6). These animals exhibited nosignificant changes in body weight over the treatment period (FIG. 7).Final tumor weight in was not significantly changed in SR-11431-treatedanimals, but the (SR-11431+metformin)-treated animals lacked anydetectable tumors at the end of the treatment period (FIG. 8).

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While the invention has been described and exemplified in sufficientdetail for those skilled in this art to make and use it, variousalternatives, modifications, and improvements will be apparent to thoseskilled in the art without departing from the spirit and scope of theclaims.

All patents and publications referred to herein are incorporated byreference herein to the same extent as if each individual publicationwas specifically and individually indicated to be incorporated byreference in its entirety.

The terms and expressions which have been employed are used as terms ofdescription and not of limitation, and there is no intention that in theuse of such terms and expressions of excluding any equivalents of thefeatures shown and described or portions thereof, but it is recognizedthat various modifications are possible within the scope of theinvention claimed. Thus, it should be understood that although thepresent invention has been specifically disclosed by preferredembodiments and optional features, modification and variation of theconcepts herein disclosed may be resorted to by those skilled in theart, and that such modifications and variations are considered to bewithin the scope of this invention as defined by the appended claims.

What is claimed is:
 1. A MCT-inhibitory compound of formula A or offormula B

wherein R¹ and R² are each independently selected from the groupconsisting of hydrogen, (C₁-C₆)alkyl, (C₃-C₆)branched alkyl,(C₃-C₇)cycloalkyl, (C₁-C₆)fluoroalkyl, a (C₆-C₁₀)aryl ring system, a 5-to 9-membered heteroaryl ring system, a (C₁-C₆)alkyl-(C₆-C₁₀)aryl ringsystem, and a (C₁-C₆)alkyl-(5- to 9-membered)heteroaryl ring system;provided that when R² comprises an aryl or heteroaryl ring system, thering system bears 0-2 independently selected substituents from the groupconsisting of fluoro, chloro, trifluoromethyl, (C₁-C₆)alkoxy, and(C₁-C₆)fluoroalkoxy; E is CH₂, CH(C₁-C₆)alkyl, or CH(C₃-C₇)cycloalkyl; Jis O, S, S(O), S(O)₂, NH, N(C₁-C₆)alkyl, or NC(═O)(C₁-C₆)alkyl; R³ is amonocyclic or bicyclic (C₆-C₁₀)aryl or a monocyclic or bicyclic (5- to10-membered) heteroaryl group wherein the aryl or heteroaryl can besubstituted or unsubstituted; R⁴ is hydrogen, (C₁-C₆)alkyl,(C₃-C₆)branched alkyl, (C₁-C₆)fluoroalkyl, (C₃-C₇)cycloalkyl, a (4- to7-membered)heteroaryl, or a monocyclic or bicyclic (C₆-C₁₀)aryl or amonocyclic or bicyclic (5- to 10-membered) heteroaryl group wherein thearyl or heteroaryl can be substituted or unsubstituted; Z is a bond, oris —O—, —CH₂—, —CH(Me)-, —S—, —NH—, or —N(C1-C6)alkyl; n=1, 2, 3, or 4;the cyclic group indicated as “ring” is an aryl or heteroaryl group ofany one of the following formulas:

wherein wavy lines indicate points of bonding, and wherein each M is anindependently selected CH or N, provided that M group is a nitrogen atomin one or two instances; G is S, O, NH, NMe, or NCF₃; T is independentlyat each occurrence CH or N; wherein R⁵ is optionally present, R⁵ beingone to four instances of independently selected F, Cl, Br, CF₃,(C₁-C₆)alkyl, OCF₃, O(C₁-C₆)alkyl, or CO—(C₁-C₆)alkyl; or, the cyclicgroup indicated as “ring” is a (C₃-C₇)cycloalkyl or a saturated (3- to7-membered)heterocyclyl comprising 1-2 heteroatoms selected from thegroup consisting of O, NH, N(C1-C6)alkyl, and N(C1-C6)fluoroalkyl;wherein the points of bonding may be cis or trans; or a pharmaceuticallyacceptable salt thereof.
 2. The compound of claim 1, wherein amonocyclic R³ is any one of

wherein X is H, (C₁-C₆)alkyl, or CF₃; and wherein Y is optionallypresent and, when present, Y is 1-3 instances of a substituent selectedfrom the group consisting of F, Cl, Br, CF₃, CH₃, Et, NH₂,NH—(CH₂)_(j)—CH₂-Q, and

wherein j=2-6, and wherein Q is one of the following groups

wherein a wavy line indicates a point of bonding.
 3. The compound ofclaim 1, wherein a bicyclic R³ is any one of

wherein X is H, (C₁-C₆)alkyl, or CF₃; and wherein Y is optionallypresent and, when present, Y is 1-3 instances of a substituent selectedfrom the group consisting of F, Cl, Br, CF₃, CH₃, Et, NH₂,NH—(CH₂)_(j)—CH₂-Q, and

wherein j=2-6, and wherein Q is one of the following groups

wherein a wavy line indicates a point of bonding, and wherein Y can bedisposed on any ring of a multi-ring system.
 4. The compound of claim 1,wherein R¹=Me, R²=i-Bu, R⁴═H, Z═CH₂, and other groups are as specifiedin claim
 1. 5. A compound of claim 4 of formula A wherein n=3.
 6. Thecompound of claim 1, wherein the compound is any one of the following,including all stereoisomeric forms, all isotopic forms, all crystallineand amorphous forms, and all pharmaceutically acceptable salt formsthereof:


7. A pharmaceutical composition comprising a compound of claim 1 and apharmaceutically acceptable excipient.
 8. A method of inhibitingmonocarboxylate transporter MCT1, monocarboxylate transporter MCT4, orboth, comprising contacting the monocarboxylate transporter with aneffective amount or concentration of a compound of claim
 1. 9. A methodof treatment of a condition in a mammal wherein treatment of thecondition with a compound having an inhibitor effect on MCT1, MCT4, orboth is medically indicated, comprising administering an effectiveamount of a compound of claim
 1. 10. The method of claim 9 wherein thecompound shows an antitumor, antidiabetes, anti-inflammatory, orimmunosuppressive pharmacological effect.
 11. The method of claim 9wherein the mammal is a human.
 12. The method of claim 9 furthercomprising administering an effective amount of a biguanide to themammal.
 13. The method of claim 12 wherein the biguanide is metformin.14. The method of claim 9 further comprising administering an effectiveamount of a standard-of-care therapeutic agent to the mammal.
 15. Themethod of claim 9 wherein administration is carried out by an oral,intravenous, intranasal or transdermal method.
 16. The method of claim 9wherein the condition is characterized by the heightened activity or bythe high prevalence of MCT1 and/or MCT4.
 17. The method of claim 16wherein the condition is cancer or type II diabetes.
 18. The method ofclaim 17 wherein the condition is cancer and the treatment follows adetermination of elevated MCT1 and/or MCT4 expression levels in thetumor or tumors.
 19. A compound of claim 1 for the treatment of amalignant tumor or tumors in humans.
 20. A compound of claim 1 for thetreatment of type II diabetes in humans.